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TWI331916B - Tuberculosis treatment - Google Patents

Tuberculosis treatment Download PDF

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Publication number
TWI331916B
TWI331916B TW092106937A TW92106937A TWI331916B TW I331916 B TWI331916 B TW I331916B TW 092106937 A TW092106937 A TW 092106937A TW 92106937 A TW92106937 A TW 92106937A TW I331916 B TWI331916 B TW I331916B
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TW
Taiwan
Prior art keywords
group
compound
hydrogen
truncated
formula
Prior art date
Application number
TW092106937A
Other languages
Chinese (zh)
Other versions
TW200403051A (en
Inventor
Ascher Gerd
Stauffer Friedrich
Berner Heinz
Mang Rosemarie
Original Assignee
Nabriva Therapeutics Ag
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Priority claimed from GB0217149A external-priority patent/GB0217149D0/en
Priority claimed from GB0217305A external-priority patent/GB0217305D0/en
Application filed by Nabriva Therapeutics Ag filed Critical Nabriva Therapeutics Ag
Publication of TW200403051A publication Critical patent/TW200403051A/en
Application granted granted Critical
Publication of TWI331916B publication Critical patent/TWI331916B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/54—Sulfur atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pulmonology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyrrole Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

A method of preventing or treating diseases caused by Mycobacterium, comprising administering to a subject in need of such treatment an effective amount of a pleuromutilin.

Description

1331916 玖、發明說明： 【發明所屬之技術領域】 本發明係關於結核病治療，譬如以截短側耳素（pleuromutilin) 治療精由分枝桿菌屬例如結核分枝桿南所媒介之疾病。 【先前技術】 結核病為一種因被結核分枝桿菌（Mycobacterium tuberculosis)感 染所媒介之慢性傳染病。結核病為開發中國家之一種主要 疾病，且在世界上已開發區域中為一項漸增之問題。雖“ 此感染可能會在一段相當可觀時間内為無徵候，但此疾病 最常以肺臟之急性發炎顯示，造成發熱及非生痰性咳嗷。 若未經治療，則典型上會造成嚴重併發症與死亡。結核病 一般可藉由抗生素療法加以控制，譬如經由以下述藥物治 療，異菸酸酊，參閱，例如Merck索引，第12版，第5203項；利 福平（Rifampicin®)，參閱，例如Merck索引，第12版，第8382項、 鏈黴素，參閱，例如Merck索引，第12版，第8983項；但主要問 題是對此種抗生素之菌株抗藥性之發展。 【發明内容】 吾人目前已發現一種化合物類型，其在治療因分枝桿菌屬 譬如結核分枝桿菌所造成之疾病上，顯示令人驚訝之活性 ，例如甚至是針對抗藥性菌株。 一方面，本發明係提供截短側耳素在製備用於治療藉由分 枝桿菌屬所媒介疾病之藥劑上之用途。 另一方面，本發明係提供一種治療藉由分枝桿菌屬所媒介 疾病之方法，其包括對需要此種治療之病患投予有效量， 84364 -6- 1331916 例如抗分枝桿菌屬有效量之截短側耳素。 分枝桿菌屬包括結核分枝捍菌。藉由分枝样菌屬所之 疾病包括分枝桿菌属感染。用於治療之截短側耳素，係勺 括-或多種截短倒耳素’例如不同截短側耳素之组合；： 療作業包括治療與預防1於根據本發明用途或用於治: =據本發明麵《截短側耳素，於後文係稱為&quot;(根據）本發 明之截短側耳素&quot;。 本發明之截短側耳素包括呈自由態驗形式之截短側耳素_， 且於存在之處，例如係呈鹽形式，呈溶劑合物形成 鹽，合物形式，及呈複合物形式，譬如環糊精複合物 發明疋截短侧耳纟可以#異構物及混合物之形式存在 二例如包括其非對映異構物及混合物。異構混合物可按適 日田方式刀離，例如根據習用方法，以獲得純異構物。本發 明係包括呈任何異構形式及任何異構混合物之根據本發·明 、Γ彳耳素，譬如在下文引述之專利文獻中所述者，該專 利又獻係以指稱方式引進本文，關於截短侧耳素之異構形 式截短素（mutilin)環中之組態，較佳係與天然產生截短素 中之組態相同。 截短側耳素為—種下式化合物1331916 玖, DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to the treatment of tuberculosis, such as diseases treated with pleuromutilin, which are mediated by mycobacteria, such as tuberculosis. [Prior Art] Tuberculosis is a chronic infectious disease caused by infection with Mycobacterium tuberculosis. Tuberculosis is a major disease in developing countries and is an increasing problem in developed regions of the world. Although “this infection may be symptomatic for a considerable period of time, the disease is most often manifested by acute inflammation of the lungs, causing fever and non-sick cough. If left untreated, it usually causes serious complications. Disease and death. Tuberculosis can generally be controlled by antibiotic therapy, for example by treatment with the following drugs, bismuth isonicotinate, see, for example, Merck Index, 12th edition, item 5203; rifampicin®, see, For example, Merck Index, 12th Edition, Item 8382, Streptomycin, see, for example, the Merck Index, 12th Edition, Item 8983; but the main problem is the development of resistance to strains of this antibiotic. [Summary] A type of compound has now been found which exhibits surprising activity in the treatment of diseases caused by mycobacteria such as M. tuberculosis, for example even against drug resistant strains. In one aspect, the invention provides truncation The use of Pleurotus in the preparation of a medicament for treating a disease mediated by Mycobacterium. In another aspect, the present invention provides a treatment by branching A method of cultivating a disease of the genus Bacillus, which comprises administering to a patient in need of such treatment an effective amount, 84364 -6-1331916, for example, an anti-mycobacterial effective amount of pleuromutilin. Mycobacteria including tuberculosis Phytophthora. The disease by the genus Mycobacterium includes Mycobacterium infection. The pleuromutilin used for treatment is a combination of - or a plurality of truncated pour hormones such as different pleuromutilin; : Therapeutic work includes treatment and prevention 1 for use according to the invention or for treatment: = according to the invention "Pleuromutilin", which is hereinafter referred to as &quot; (according to) the pleuromutilin of the invention. The pleuromutilin of the present invention comprises pleuromutilin in a free form, and is present, for example, in the form of a salt, in the form of a solvate, in the form of a salt, in the form of a complex, such as in the form of a complex, such as The cyclodextrin complex invention may be in the form of an isomer and a mixture, for example, including its diastereomers and mixtures. The isomeric mixture may be cleaved in a suitable manner, for example, according to conventional methods. To obtain pure isomers. The present invention includes any isomeric form and any isomeric mixture according to the present invention, which is described in the patent documents cited below, and the patent is also incorporated herein by reference. The configuration of the isomeric form of the short-acting auris in the mutilin loop is preferably the same as in the naturally occurring truncated hormone. The pleuromutilin is a compound of the following formula

84364 1331916 其係為一種天然生成之抗生素，例如， 1 ΖΤ)1 擔子諸綱截短侧 + (Pleurotus mutilus)與 passeckerianus 側耳所庙吐 Α -、 # ^ ίο ιίκ ** 參閱’例如 Merck 索^弟12版，弟7694項。已發展出多種具有截短側耳 要¥結構且具有例如抗細菌活性之其他截短側耳素*、 本發明之截短側耳素包括一種截短側、 ^ I其具有如化學 式中所列tf之基本結構元素84364 1331916 The system is a naturally occurring antibiotic, for example, 1 ΖΤ) 1 scorpion genus truncated side + (Pleurotus mutilus) and passeckerianus lobster temple spitting -, # ^ ίο ιίκ ** See 'eg Merck 12 edition, brother 7694. A variety of other pleuromutilin having a truncated side ear structure and having, for example, antibacterial activity have been developed, and the pleuromutilin of the present invention comprises a truncated side, ^I having the basic tf as listed in the chemical formula Structural element

PLEU Ο 其中R為乙晞基或乙基，且虛線為—個鍵結或無鍵結 下列編號系統係使用於本申請案中：PLEU Ο where R is an ethylidene group or an ethyl group, and the dotted line is a bond or no bond. The following numbering systems are used in this application:

00

PLEU 介於位置19與20間（及介於位置丨與2之間）之虛線為一個 鍵結或無鍵結。在式A或式PLEU化合物中，環系統之位置4 、7及/或8中之一個氫原子可被氘置換，且若介於位置1與 2間之虛線為無鍵結（單鍵介於位置丨與2之間），則此環系統 可進一步在位置1及/或2上被取代，例如被鹵素、氘或羥 基。在位置14上之基團係進一步被取代，較佳係被經取 代之羧基。 84364 1331916 根據本發明截短侧.耳素之實例，包括例如 -一種如在US3716579中所揭示之化合物，例如具有下式The dotted line of PLEU between positions 19 and 20 (and between position 丨 and 2) is a bond or no bond. In the compound of formula A or formula PLEU, one of the hydrogen atoms at positions 4, 7, and/or 8 of the ring system may be replaced by hydrazine, and if the dotted line between positions 1 and 2 is unbonded (a single bond is between The position of the ring system can be further substituted at position 1 and/or 2, for example by halogen, hydrazine or hydroxyl. The group at position 14 is further substituted, preferably a substituted carboxyl group. 84364 1331916 An example of a truncated side otoxin according to the invention, comprising, for example, a compound as disclosed in US Pat. No. 3,716,579, for example having the formula

其中 R 為 CH3 -(CH! )7 -CH=CH-(CH2 )7 -COO-、ch3 _(ch2 )4 -ch=cTh-ch2-ch;ch-(ch2)7-coo-、ch3-(ch2)9-ch=ch-(ch2)7-coo-或 氣； -一種如在GB1312148中所揭示之化合物，例如具有下式Wherein R is CH3 -(CH!)7 -CH=CH-(CH2)7-COO-, ch3 _(ch2)4 -ch=cTh-ch2-ch;ch-(ch2)7-coo-,ch3- (ch2) 9-ch=ch-(ch2)7-coo- or gas; - a compound as disclosed in GB1312148, for example having the formula

其中X、Y及Z均如任一個下列基團中之定義： a. X 為-CO-CHa-Ri，其中 1^為 Η、Cl、Br、I、氰硫基、疊 氮基、（N，N-四亞曱基-胺硫甲醯基）-巯基、二硫羥碳酸-CHCk)烷基、-S-苯基，被羧基或被一或兩個0H取代之 S-苯基，-S-吡啶基' -S-芊基' -SJCu)烷基，或被一或 多個胺基、0H或羧基取代之-S-(Ci -5)烷基，Y為乙烯基 ，及Z為Η ; b. X為-CO-CO-OH，Υ為乙烯基，及Ζ為Η; c. X為-COCH3，Υ為乙烯基，及Ζ為Η; 84364 -9- 1331916 d. X為COCH2NH2，Y為乙基，及Z為Η; e. X為下式基團Wherein X, Y and Z are as defined in any of the following groups: a. X is -CO-CHa-Ri, wherein 1^ is Η, Cl, Br, I, thiocyanyl, azide, (N , N-tetradecyl-amine thiomethionyl)-fluorenyl, dithiol-carbonate-CHCk)alkyl, -S-phenyl, S-phenyl substituted by carboxyl or substituted with one or two 0H, - S-pyridyl '-S-fluorenyl'-SJCu)alkyl, or -S-(Ci-5)alkyl substituted by one or more amine groups, 0H or carboxyl group, Y is a vinyl group, and Z is b. X is -CO-CO-OH, hydrazine is vinyl, and hydrazine is hydrazine; c. X is -COCH3, hydrazine is vinyl, and hydrazine is hydrazine; 84364 -9- 1331916 d. X is COCH2NH2 , Y is ethyl, and Z is hydrazine; e. X is a group of the formula

，Y為乙基，及Z為Η ; f. X為Η，Υ為乙烯基，及Ζ為乙醯基；或 g. X為COR2，其中R_2為（q _5 )燒基，γ為乙埽基，及ζ為η -一種如在US4278674中所揭示之化合物，例如具有下式, Y is ethyl, and Z is Η; f. X is Η, Υ is vinyl, and Ζ is acetonitrile; or g. X is COR2, where R 2 is (q _5 ) alkyl and γ is acetyl a group, and ζ is η - a compound as disclosed in US Pat. No. 4,278,674, for example having the formula

其中R!為乙埽基或乙.基，η為整數2至5，χ為硫或基團-γ_ 次苯基-Ζ-或基團，丫與2均為硫，或丫與2之一為硫 ，而另一個為氧，心為Η或式LUS4278674之第二個截短-素 %其中Rl係如上文定義，且經由位置14上之-〇_c〇-CH2 _ 基團連接；叫與113係（互相獨立）為（Ch〇)垸基，或尺2與 3和氮原子起形成四氫吡咯基、六氫吡啶基、嗎福啉 基、硫代嗎福啉基或丨_六氫_1H_一氮七圜烯基，或&amp;與&amp; 和氮原子—起形成六氫1Ή基，其中第二個氮原子係被 (ChI基、（C1M)搜燒基、炔醯基氧基烷基或 苯甲醯氧基（C1_4)烷基取代，或 1係如上文疋義’ n = 2，心為％ ^烷基、（Cl_4)羥烷基 (匸2-5)块^基氧基燒基或苯甲酿氧基υ烷基， X為_NR4 ’ JL r2與Ri4 —起形成介於氮原子間之次乙基橋 84364 1331916 ;譬如 Μ-脫氧-14[(2-二乙胺基乙基)絲乙醯氧基]截短素，例女 亦稱為具有下式之提耳目林(Tiamulin)Wherein R! is an ethylidene group or a B group, η is an integer of 2 to 5, hydrazine is a sulfur or a group -γ_phenylene-fluorene- or a group, and hydrazine and 2 are both sulfur, or one of hydrazine and 2 Is sulfur, and the other is oxygen, the heart is Η or the second truncation-% of the formula LUS4278674, wherein Rl is as defined above, and is linked via the -〇_c〇-CH2 _ group at position 14; And the 113 series (independently independent) are (Ch〇) fluorenyl groups, or the quaternary 2 and 3 and nitrogen atoms form tetrahydropyrrolyl, hexahydropyridyl, morpholinyl, thiomorpholine or 丨_hexa Hydrogen-1H_-nitros-7-alkenyl, or &amp; with &amp; and nitrogen atom to form a hexahydroindolyl group, wherein the second nitrogen atom is (ChI group, (C1M) search base, alkyne group Aldooxy or benzylideneoxy (C1_4) alkyl substituted, or 1 is as defined above, 'n = 2, core is % ^ alkyl, (Cl 4 )hydroxyalkyl (匸 2-5) block ^ Alkoxyalkyl or benzyloxyalkylene, X is _NR4 'JL r2 together with Ri4 forms a secondary ethyl bridge between the nitrogen atoms 84464 1331916; such as Μ-deoxy-14[(2- Diethylaminoethyl)silyloxy] truncation, also known as Tia) with the following formula (Tia) Mulin)

-一種如在US413〇7〇9中所揭示之化合物，例如具有下式a compound as disclosed in US Pat. No. 7,9,9, for example having the formula

其中R為乙基或乙晞基’ R〗係選自哌喃己糖、呋喃己糖、 喊喃戊.糖、吱喃戊糖、P底喃糖及吱喃糖胺基糖^二酿.·、 二糖之α-或谷-異頭物，且R2為Η、苯曱醯基或（c24)烷醯 基，或為2-脫氧-2-(幾亞胺基）-3,4,6-三-0-乙醯基音D·喊喃 葡糖基或-半乳17瓜喃糖基、2-脫氧-2-(經亞胺基）_ α-D-半乳喊 喃糖基、2-脫乳-2-胺基-4,6-二-〇-乙酿基-展喃葡糖基或 2-脫氧-2-乙醯胺基-3,4,6-三-Ο-乙醯基 a_D-p底喃葡糖基，且&amp; 為Η ; -一種如在US4129721中所揭示之化合物，例如具有下式Wherein R is ethyl or ethoxyl group 'R> is selected from the group consisting of meptonose, furan hexose, sulphonate, sugar, pentose, pentose, and sucrose. · Alpha- or gluten-anomeric of disaccharide, and R2 is hydrazine, phenylhydrazino or (c24) alkanoyl, or 2-deoxy-2-(amilimino)-3,4, 6-three-0-Ethyl fluorene D· 喃 glucosyl or - galactose 17 guanosyl, 2-deoxy-2-(imido) _ α-D-half sucrose 2-defotho-2-amino-4,6-di-indole-ethyl-glycosyl-glucopyranosyl or 2-deoxy-2-acetamido-3,4,6-tri-anthracene-B Indenyl a_D-p glucopyranosyl, and &amp; is a hydrazine; a compound as disclosed in US 4,219,721, for example having the formula

1331916 與其19,20-二氫衍生物，及其四（C2-6)烷醯基衍生物； -一種如在EP0013768中所揭示之化合物，例如具有下式1331916 and its 19,20-dihydro derivative, and its tetrakis(C2-6)alkylhydrazine derivative; a compound as disclosed in EP 0 013 768, for example having the formula

其中Ri為乙烯基或乙基，m為0或1，及R2為雜環基，其 中含有一或多個選自0、S及N雜原子之5-或6-員不飽和 或飽和」雜環，係連接至-S(CH2)m-基團； -一種如在EP0153277中所揭示之化合物，例如N-醯基-14-0-[(l-胺基-2-甲基丙-2-基）硫乙醯基]-截短素或19,20-二氫截短素 ，譬如具有下式Wherein Ri is a vinyl or ethyl group, m is 0 or 1, and R 2 is a heterocyclic group containing one or more 5- or 6-membered unsaturated or saturated heteroatoms selected from the group consisting of 0, S and N heteroatoms a ring attached to the -S(CH2)m- group; a compound as disclosed in EP 0153277, for example N-mercapto-14-0-[(l-amino-2-methylpropan-2) -yl)thioethyl]- truncated or 19,20-dihydro truncated, for example having the formula

其中心為乙烯基或乙基（位置19與20)，且R2為視情況經羥 基取代之胺基烷基或5-員飽和雜環，例如包括具有下式 之華臬目林(Valnemulin)(Econor®)Its center is a vinyl group or an ethyl group (positions 19 and 20), and R2 is an amino group-substituted aminoalkyl group or a 5-membered saturated heterocyclic ring as the case may be, for example, including Valnemulin having the following formula (Valnemulin) Econor®)

84364 -12- 1331916 -一種如在US516526中所揭示之化合物，例如具有下式84364 -12- 1331916 - a compound as disclosed in US516526, for example having the formula

其中&amp;與R2係互相獨立為Η、烷基、烯基、環烷基、芳 基或芳燒基； -一種如在W09322288中所揭示之化合物，例如具有下式Wherein &amp; and R2 are independently of each other a hydrazine, alkyl, alkenyl, cycloalkyl, aryl or aryl group; a compound as disclosed in W09322288, for example having the formula

其中心與R2係互相獨立為Η、烷基，或&amp;與R2和彼等所連 接之碳原子一起為環烷基；且R3與心係互相獨立為Η、 烷基或經取代之燒基； -一種如在WO9725309中所揭示之化合物，例如具有下式The center and R2 are independently of each other, 烷基, alkyl, or &amp; and R2 together with the carbon atom to which they are attached are cycloalkyl; and R3 and the core are independent of each other, an alkyl group or a substituted alkyl group. a compound as disclosed in WO9725309, for example having the formula

其中Υ為胺甲醯基氧基，其中Ν-原子為未經取代或經單-或二-取代，譬如下式化合物 84364 -13- 1331916Wherein hydrazine is an aminomethyl methoxy group, wherein the oxime atom is unsubstituted or mono- or di-substituted, and the compound of the formula 84364 -13- 1331916

其中Ri為乙烯基或乙基’〜與心係互相獨立為Η，或視情 況經取代之 -飽和或不飽和（Ci·6)烴或（&lt;::3_8)環狀烴， -雜環基或芳基，或 - R2與1_一起形成3至8個環原子之視情況經取代之環狀基 團， 視情況含有一個選自N、〇及s之其他雜原子，且視情況 稠合至烴環、雜環族基團或芳族基團；或 尺2為上又單價基團之一，且化為選自s〇2R4、c〇R5、〇r5 及之基團；其中 ·- I為視情況經取代之 -飽和或不飽和（C丨_0)烴或（c3_8)環狀烴， -雜環基、芳基、（Cu)烷胺基或芳胺基； R5為視情況經取代之 -飽和或不飽和（&lt;：卜6)烴或（c3-8)環狀烴， _雜每基或芳基， h與R·/係互相獨立為Η或視情況經取代之 -飽和或不飽和（Cu)烴或（c3_8)環狀烴， _雜環基或芳基，或 心與R?和彼等所連接之氮原子—起形成视情況經取代之 84364 -14- (C3-8)環狀基團，視情況含有一個選自N、0或S之其他雜 原子，且視情況稠合至烴環、雜環或芳族基團； -一種如在WO9805659中所揭示之化合物，例如具有下式Wherein Ri is a vinyl or ethyl '~ and the core is independent of each other, or optionally substituted - saturated or unsaturated (Ci. 6) hydrocarbon or (&lt;: 3-8) cyclic hydrocarbon, - heterocyclic ring Or a aryl group, or - R2 and 1_ together form an optionally substituted cyclic group of 3 to 8 ring atoms, optionally containing a hetero atom selected from N, hydrazine and s, and optionally thick Or a hydrocarbon ring, a heterocyclic group or an aromatic group; or the rule 2 is one of the above monovalent groups, and is selected from the group consisting of s〇2R4, c〇R5, 〇r5 and the like; - I is optionally substituted with a saturated or unsaturated (C丨_0) hydrocarbon or a (c3_8) cyclic hydrocarbon, a heterocyclic group, an aryl group, a (Cu) alkylamino group or an arylamine group; R5 is a visual Substituted - saturated or unsaturated (&lt;:b 6) hydrocarbon or (c3-8) cyclic hydrocarbon, _hetero per aryl or aryl, h and R·/ are independent of each other or are optionally substituted a saturated or unsaturated (Cu) hydrocarbon or a (c3_8) cyclic hydrocarbon, a heterocyclic or aryl group, or a heart and a nitrogen atom to which R? and the other are bonded, forming an optionally substituted 84364-14 - (C3-8) a cyclic group, optionally containing one selected from N, 0 or S Other heteroatoms, and optionally fused to a hydrocarbon ring or a heterocyclic aromatic group; - one of the compounds disclosed in WO9805659, such as the, for example, having the formula

其中心為乙烯基或乙基，且R2為基團R3、R4CH2-或RsR^CI^Cii-，其中4 R3與R4為氮雙環狀環系統，或R5與心和彼等所 連接之碳原子一起形成氮雙環狀環系統； -W09821855之一種化合物；例如具有下式Its center is vinyl or ethyl, and R2 is a group R3, R4CH2- or RsR^CI^Cii-, wherein 4 R3 and R4 are nitrogen double ring systems, or R5 and the heart and the carbon to which they are attached The atoms together form a nitrogen double-ring ring system; a compound of -W09821855; for example having the formula

其中11與111係互相獨立為0、1或2; X為Ο、S、S(O)、S02 、-COO-、-NH-、-CONH-、-NHCONH-或一個鍵結；K 為乙 烯基或乙基；R2為非芳族單環狀或雙環狀基團，含有一 或兩個驗性氮原子，並經過環碳原子連接，例如R2為視 情況經取代之喵啶基、氮雙環并[2.2.1]庚基、氮雙環并[4·3·0] 壬基、氮雙環并[3.2.1]辛基、氮雙環并[3.3.0]辛基、氮雙環 并[2.2.2]辛基、氮雙環并[3.2.1]辛烯基、氮雙環并[3.3.1]壬基 或氮雙環并[4.4.0]癸基；R3為Η、ΟΗ ;或在ΙΑ或ΙΒ之14位 置處之部份基團 R2 (CH2 )m X(CH2 )n CH2 COO 係被 &amp; Rb C=CHCOO 84364 -15- 1331916 置換，其中Ra或Rb之一為氫，而另一個為R2 ;或Ra與Rb 一起形成R2 ; -一種如在W00007974中所揭示之化合物，例、如具有2-氟基 取代基之截短素或19,20,二氫截短素之14-醯氧基衍生-物， 譬如具有下式Wherein 11 and 111 are independently 0, 1 or 2; X is Ο, S, S(O), S02, -COO-, -NH-, -CONH-, -NHCONH- or a bond; K is ethylene Or an ethyl group; R2 is a non-aromatic monocyclic or bicyclic group containing one or two inert nitrogen atoms bonded through a ring carbon atom, for example, R2 is an optionally substituted acridinyl group, nitrogen Bicyclic [2.2.1] heptyl, nitrogen bicyclo[4·3·0] fluorenyl, nitrogen bicyclo[3.2.1]octyl, nitrogen bicyclo[3.3.0]octyl, nitrogen bicyclo[2.2 .2] octyl, nitrogen bicyclo[3.2.1]octenyl, nitrogen bicyclo[3.3.1]fluorenyl or nitrogen bicyclo[4.4.0]fluorenyl; R3 is hydrazine, hydrazine; or in hydrazine or A portion of the group R2 (CH2)m X(CH2)n CH2 COO at position 14 is replaced by &amp; Rb C=CHCOO 84364 -15-1331916, wherein one of Ra or Rb is hydrogen and the other is R2; or Ra together with Rb to form R2; - a compound as disclosed in W00007974, for example, a truncated hormone having a 2-fluoro substituent or a 19, 20, dihydro-tertimeric 14-anthracene Derivatives, such as having the following formula

其中R!為乙烯基或乙基（位置19與20)，且R2COO-為醯氧 基，例如 H0CH2C02-或 R-X-CH2C02，其中 X為 Ο、S或NR' ，且R與R'係互相獨立為脂族或芳族基團，R2COO-較佳 為胺甲嬷基，譬如基團R3R4NC02-，其中R3與R4具有不·同 意義（例如R3與R4具有如在WO9725309中所揭示關於R2與R3 之意義）； -一種如在W00027790中所揭示之化合物，例如下式化合物Wherein R! is a vinyl group or an ethyl group (positions 19 and 20), and R2COO- is a decyloxy group, such as H0CH2C02- or RX-CH2C02, wherein X is oxime, S or NR', and R and R' are independent of each other. R2COO- is preferably an amine carbenyl group, such as the group R3R4NC02-, wherein R3 has the same meaning as R4 (for example R3 and R4 have R2 and R3 as disclosed in WO9725309 Meaning) - a compound as disclosed in W00027790, such as a compound of the formula

其中&amp;為RA(CH2)n(CH2)m、RA(CH2)p或下式基團 84364 -16- 1331916 &lt;vv H2其中R為螺·稠合單-或雙環狀環，含有一或兩 ㈣性N_原子；Xlh可為相同或不同，各為偶-或= ’其條件是m2之至少—個為.㈣；且y為视、,、 或-CH2 _CH2 - ; RA為视情況經取代之芳基或經由碳原子連 結之雜芳基；例如，Ra為視情況經取代之苯基”塞吩基 、吡啶基、呋喃基、嘍唑基、異噚唑基、苯并咪唑基： 峻0林基、1，2,3,4-四氳-異„奎„林基或苯并p塞峻基： m為1、_2或3; η為〇、lil2; ρΛ1至4;匕為乙缔基或己 基；及R3為Η、0H或F，且心為！！；或R3*H，且心為^ 一種如在W00037074中所揭示之化合物，例如下式化合物Wherein &amp; is RA(CH2)n(CH2)m, RA(CH2)p or a group of the following formula 84364-166-131916 &lt;vv H2 wherein R is a spiro-fused mono- or bicyclic ring containing one Or two (four) N_ atoms; Xlh may be the same or different, each is even- or = 'the condition is that at least one of m2 is . (four); and y is visual, , or -CH2 _CH2 - ; RA is visual a substituted aryl group or a heteroaryl group bonded via a carbon atom; for example, Ra is optionally substituted phenyl exemplified, pyridyl, furyl, carbazolyl, isoxazolyl, benzimidazole Base: Jun 0 forest base, 1, 2, 3, 4-tetrazole-iso „ Kui lin lin or benzopyrene: m is 1, _2 or 3; η is 〇, lil2; ρ Λ 1 to 4;匕 is an ethyl or hexyl group; and R3 is Η, 0H or F, and the heart is !!; or R3*H, and the heart is ^ a compound as disclosed in W00037074, such as a compound of the formula

cr 其中&amp;為視情況經取代之雜芳基，其包含5_員雜芳族環 ，其具有至少一個N-原子，例如p比洛、p比嗤、咪峻、} 2 3_ 三唑、1，2,4-三唑、吲哚、苯并咪唑、苯并三唑、2_氮⑷ 哚或6-氮啕哚；且其係經由N-原子連結；&amp;為乙埽基或乙 基；R3為Η、0H或F，且R4為H;或尺3為Η，且&amp;為 -一種如在WO0073287中所揭示之化合物，例如下式化合物 84364 -17- 1331916Cr wherein &amp; is optionally substituted heteroaryl, which comprises a 5-membered heteroaromatic ring having at least one N-atom, such as p, pi, p, 咪, 2 2 3 _ triazole, 1,2,4-triazole, anthracene, benzimidazole, benzotriazole, 2-nitro (4) anthracene or 6-azaindole; and it is linked via an N-atom; &amp; is ethyl acetonitrile or R3 is Η, 0H or F, and R4 is H; or Rule 3 is Η, and &amp; is - a compound as disclosed in WO0073287, for example, compound 84364-17-1331916

其中R!為視情況經取代之芳基，例如氮雙環并·辛基；或 視情況經取代之含氮環’例如六氫p比咬基；R2為乙缔其 或乙基，R3為Η、0H或F ’且心為！};或R3gH，且1^為|?. -一種如立W00114310中所揭示之化合物，例如下式化人物 ' .、'、ch,〇hWherein R! is an optionally substituted aryl group, for example, a nitrogen bicyclo-octyl group; or a nitrogen-containing ring which is optionally substituted, for example, a hexahydro-p-bite group; R2 is an ethyl or an ethyl group, and R3 is a hydrazine. , 0H or F 'and heart! }; or R3gH, and 1^ is |?. - a compound as disclosed in 立立 W00114310, for example, the following character ' ., ', ch, 〇h

其中.為含氮雜環、視情況經取代之芳基或視情況經取 代之雜芳基，或CH2R5， 例如R!為視情況經取代之苯基、3-吡啶基、4-吡咬基、响 唉-2-基、l，3,4-p塞二嗤-2-基、苯并p塞峻-2-基。2H-1，2,4-三吨·3_ 基、氮雙環庚基、氮雙環辛基或六氫吡啶基；尺2為乙少希 基或乙基；R3為Η、0Η或F，且心為Η;或R3為Η，且^ 為F，&amp;為鹵素或SR^ ;及為胺基坑基' 含氮雜環或視 情況經取代之芳基或視情況經取代之雜芳基；例如，&amp; 為視情況經取代之苯基、3-p比咬基、4-p比咬基、喝咬_2_基 、1，3,4-嘧二唑-2-基、苯并嘍唑_2-基、2H-1，2,4-三唑_3·基、 亂雙壤庚基、氮雙環辛基或六氮比咬基； 84364 -18- 1331916 -一種如在W00109095中所揭示之化合物，例如下式化合物Wherein a nitrogen-containing heterocyclic ring, an optionally substituted aryl group or an optionally substituted heteroaryl group, or CH2R5, for example, R! is optionally substituted phenyl, 3-pyridyl, 4-pyridyl , fluoren-2-yl, l,3,4-p-dioxa-2-yl, benzo-p-sept-2-yl. 2H-1,2,4-three tons·3_ group, nitrogen bicycloheptyl, nitrogen bicyclooctyl or hexahydropyridyl; rule 2 is acetylcholine or ethyl; R3 is Η, 0Η or F, and Is Η; or R3 is Η, and ^ is F, &amp; is halogen or SR^; and is an amine-based heterocyclic nitrogen-containing or optionally substituted aryl or optionally substituted heteroaryl; For example, &amp; is optionally substituted phenyl, 3-p ratio bite base, 4-p ratio bite base, drink bite 2_ base, 1,3,4-pyrazol-2-yl, benzo Carbazole-2-yl, 2H-1,2,4-triazole-3-yl, chaotic double-heptyl, nitrogen bicyclooctyl or hexanitro-bite; 84364 -18- 1331916 - as in W00109095 a compound disclosed, such as a compound of the formula

其中R為氫或烷基；心為氫或下式基團 其中X為S、0或NR1() 其中R10為Η或烷基，或 Ν+(Ι^ 〇)2，其中R’1()為烷基，於適當陰離子存在下；且&amp; 為胺基 '烷基、芳基、雜環基或巯基；及若X為氧，則^ 另外為氫’ &amp;為次芳基’例如次苯基；或次雜環基；心 為虱或·燒基；R5為氫或燒基；R3、r3 '、心、r7及&amp;係.互 相獨立為氫或氘；或R與Rz和彼等所連接之氮原子一起形 成非芳族次雜環基，及R!為下式基團 其中X與均如上文定義；例如下式化合物Wherein R is hydrogen or alkyl; the heart is hydrogen or a group of the formula wherein X is S, 0 or NR1() wherein R10 is hydrazine or alkyl, or Ν+(Ι^ 〇)2, wherein R'1() Is an alkyl group in the presence of a suitable anion; and &amp; is an amino group 'alkyl, aryl, heterocyclic or fluorenyl; and if X is oxygen, ^ is additionally hydrogen ' &amp; is a arylene' Phenyl; or subheterocyclyl; heart is ruthenium or ruthenium; R5 is hydrogen or alkyl; R3, r3 ', heart, r7 and &amp; are independent of each other as hydrogen or hydrazine; or R and Rz and The nitrogen atom to be bonded together forms a non-aromatic heterocyclic group, and R! is a group of the formula wherein X and are as defined above; for example, a compound of the formula

84364 -19- 1331916 其中Rls為氫或下式基團84364 -19- 1331916 wherein Rls is hydrogen or a group of the formula

其中R05為氫或氘；Rh為氫、甲I 4 〃 允 . &gt; u y基或第三·丁基 ，Rh為氫或曱基；且Rh、1^及1^為氫或氘. 一種如在WO0174788中所揭示之化合物，右丨’ 口物，例如下式化合物Wherein R05 is hydrogen or hydrazine; Rh is hydrogen, methyl I 4 〃 允. &gt; uy or tributyl, Rh is hydrogen or sulfhydryl; and Rh, 1^ and 1^ are hydrogen or hydrazine. a compound disclosed in WO0174788, a right-handed substance, such as a compound of the formula

例如吡啶、嗒畊、嘧啶、吡畊、異噚唑、嘍唑 '咪唑' 吡唑、1，2,3-二唑、1，2,4-三唑、苯并咪吐、3_酮基-3,4二氫 峨啶并{2,3-冲比畊或吡唑并[l，5-a]嘧啶；及r2為乙烯基或-乙 基； 其中心為5-或6-員視情況經取代之雜芳基； -一種如在W00204414中所揭示之化合物，例如選自以下之 化合物，14-0-[(環烷基-硫基）乙醯基]截短素；14-〇-[(環烷基 -烷基-硫基）乙醯基]截短素；14-0-[(環烷氧基）乙醯基]截短 素；或14-0-[(環烷基-烷氧基）乙醯基]截短素，譬如具有下式For example, pyridine, argon, pyrimidine, pyridin, isoxazole, carbazole 'imidazole' pyrazole, 1,2,3-diazole, 1,2,4-triazole, benzimid, 3-keto -3,4 dihydroacridine and {2,3-crushed or pyrazolo[l,5-a]pyrimidine; and r2 is vinyl or -ethyl; its center is 5- or 6-membered a substituted heteroaryl group; a compound as disclosed in W00204414, for example a compound selected from the group consisting of 14-0-[(cycloalkyl-thio)ethenyl] truncated; 14-〇 -[(cycloalkyl-alkyl-thio)ethenyl] truncated; 14-0-[(cycloalkoxy)ethenyl] truncated; or 14-0-[(cycloalkyl) - alkoxy)ethinyl] truncated, for example having the formula

84364 -20- 1331916 其中R為氯；Rl為氫或下式基團84364 -20- 1331916 wherein R is chlorine; R1 is hydrogen or a group of the formula

X II 其中X為硫、氧或m ，並 為胺基、燒基H〜二:1Q為氫或垸基；且119 為氮.Y… 環基；及若X為氧，則巧另外 = :: R2為氫或一或多個取代基，〜為氫 或:ί元基’ 115為風或燒基 R » ρ Α ^ -Κ - 3為虱、汛或鹵素，116、 8 ；&quot;;m4選自G至4之數目；η為選自0至1〇 數目及ρ為選自〇至1〇之數目；其附帶條件是，η如 上ρ為至少1 ;例如下式化合物X II wherein X is sulfur, oxygen or m, and is an amine group, a halogen group H~2: 1Q is hydrogen or a fluorenyl group; and 119 is a nitrogen. Y... ring group; and if X is oxygen, then another =: : R 2 is hydrogen or one or more substituents, ~ is hydrogen or: ί aryl ' 115 is wind or alkyl R » ρ Α ^ - Κ - 3 is 虱, 汛 or halogen, 116, 8; &quot;; M4 is selected from the number of G to 4; η is a number selected from 0 to 1 及 and ρ is a number selected from 〇 to 1 ;; with the proviso that η is as above ρ is at least 1; for example, a compound of the formula

其中Rlp為氫或胺基酸之殘基； -一種如在W00212199中所揭示之仆人札 .,, 吓勻〈化σ物，例如下式化合物Wherein Rlp is a residue of hydrogen or an amino acid; - a servant as disclosed in W00212199, which is a compound of the formula

其中心為： -經由環碳原+連接之5_或6_員彡族或雜芳族環，較佳 為峨症基，且包含選自自基、R7〇·、R?s或㈣Ν之 84364 -21 - 取代基，於鄭近連接碳之環碳上；或 -5-或6-員二氫雜芳族環，經由環碳原子連接，並包含 一個氧或一或兩個氮原子，且視情況稠合至苯基，5_ 或6-貝雜芳基環’其包含—或雨個氮原子，或5_或6_員 雜環基環，其包含硫、氧或氮原子，且進一步包含選 自銅基或硫酮基之取代基，於鄰近連接碳之環碳上； _經由環碳原子連接之6-員四氫雜芳族環，其包含一或 兩個氮原子’且進一步包含兩個獨立選自酮基或硫ΐ同 基之·取代基’其中取代基之一係在鄰近連接碳之環碳 上；或 -雙環狀雜芳基環，經由環碳原子連接，並包含九或十 個環原子及一至四氮原子； 其中I之環可視情況進一步被取代；r2為乙烯基或乙基 ;R3為η、0H或F ’且R4為η，或R3為Η，且心為卩；及R5 與化一起形成酮基；或仏與^各為Η ’且心為^或OH， 及為Η，或心為！！，且心為Η或OH;尺7為視情況經取代 之（Cl - 6 )燒基，及R8與Rg係獨立選自氫或視情況經取代之 (q-6)烷基。 -一種如在W00222580中所揭示之化合物，具有下式The center is: - a 5- or 6-membered steroid or heteroaromatic ring attached via a ring carbonogen +, preferably a sputum base, and comprising a group selected from the group consisting of a radical, R7〇, R?s or (d) 84364 -21 - a substituent attached to the carbon ring carbon of Zheng Jin; or a 5- or 6-membered dihydroheteroaromatic ring bonded via a ring carbon atom and containing an oxygen or one or two nitrogen atoms, And optionally fused to a phenyl group, a 5- or 6-beta heteroaryl ring containing - or a nitrogen atom, or a 5 or 6 membered heterocyclyl ring containing a sulfur, oxygen or nitrogen atom, and Further comprising a substituent selected from a copper group or a thioke group on a ring carbon adjacent to the carbon; a 6-membered tetrahydroheteroaromatic ring bonded via a ring carbon atom, which contains one or two nitrogen atoms' Further comprising two substituents independently selected from keto or thioindoles, wherein one of the substituents is attached to a ring carbon adjacent to the carbon; or a bicyclic heteroaryl ring is attached via a ring carbon atom, And comprising nine or ten ring atoms and one to four nitrogen atoms; wherein ring I is further substituted; r2 is vinyl or ethyl; R3 is η, 0H or F' and R4 is η, or R3 is Η, and the heart is 卩; and R5 forms a ketone group together with chemistry; or 仏 and ^ each are ’ ' and the heart is ^ or OH, and is Η, or the heart is! ! And the core is ruthenium or OH; the ruthenium 7 is an optionally substituted (Cl - 6 ) alkyl group, and the R8 and Rg are independently selected from hydrogen or optionally substituted (q-6) alkyl. a compound as disclosed in W00222580 having the formula

84364 • 11 · 1331916 其中R與&amp;和彼等所連接之氮原子一起形成四氫吡咯基戈 六氫吡啶基，Ri為下式基團 ~一 4,r I及I為虱、汛或鹵素，心為氫或烷基，心為氦 或燒基，心、心及尺8為氫或気；心為胺基、烷基、芳基 、雜環基或毓基；且若X為氧，則Rp另外為氫；心〇1畫 或烷基，R，! 〇為烷基，X為硫、氧、服 、’ ’ ‘飞 適當陰離子存在下，γ為硫或氧，及 其附帶滌件是’當MR2和彼等所連接之氮原子一起 六氫吨咬基，爪為0 ’ Y為S，Η係連接在該六氫一 之位置3上時，經由殘基γ連接至六氫吡啶環之該式!： 團，係無論是呈⑻-組態或呈Κ態，較佳係呈孙組能 ;較佳為下式化合物84364 • 11 · 1331916 wherein R together with the nitrogen atom to which they are attached form a tetrahydropyrrolyl hexahydropyridyl group, Ri is a group of the formula -4, and r I and I are ruthenium, osmium or halogen. , the heart is hydrogen or alkyl, the heart is strontium or alkyl, the heart, heart and rule 8 are hydrogen or hydrazine; the heart is an amine group, an alkyl group, an aryl group, a heterocyclic group or a fluorenyl group; and if X is oxygen, Then Rp is additionally hydrogen; heart 〇 1 draw or alkyl, R, ! 〇 is alkyl, X is sulfur, oxygen, service, ' ' fly in the presence of a suitable anion, γ is sulfur or oxygen, and its accompanying polyester It is 'when MR2 and the nitrogen atom to which they are attached together with a hexahydro ton bite, the claw is 0' Y is S, and the lanthanide is attached to the hexahydro-position 3, and is attached to the hexahydropyridine via the residue γ. This type of ring!: The group, whether it is in (8)-configuration or in the state of enthalpy, is preferably a group of compounds; preferably a compound of the formula

—Μ ^ i 為氳或-或多個取代基，及若經由硫原子連接至六u 啶環之基團係在該六氫吡啶環之位置3上， 且K5 ρ為風時 Ρ 吡 ，則連接至硫原子之基團係Α β β 因你共6田疋呈（S)-組態或呈（R). 84364 •23· 1331916 態； 下式化合物—Μ ^ i is hydrazine or — or a plurality of substituents, and if the group attached to the hexa- pyridine ring via a sulfur atom is at position 3 of the hexahydropyridine ring, and K 5 ρ is 风 pyr in the wind, then The group 连接 β β attached to the sulfur atom is a (S)-configuration or a (R). 84364 •23· 1331916 state;

lq-WO〇222580 其中 R3q、R'3q、R^q、R7q 及 R8q 為相應於 &amp;、％、&amp;、&lt; 及Rs之讨旨數，如關於式I-W00222580化合物所定義者.r 為氫或一或多個取代基’較佳為氫；及\為若幾基被分 裂開來，而仍然留下之胺基酸部份； 下式化合物lq-WO〇222580 wherein R3q, R'3q, R^q, R7q and R8q are the corresponding numbers corresponding to &amp;, %, &amp;, &lt; and Rs, as defined for the compound of formula I-W00222580. r is hydrogen or one or more substituents 'preferably hydrogen; and \ is an amino acid moiety which is left if the group is split;

其中R3r、R’3r、kk、^及‘為相應於R3、％、&amp; 、心、R7及Rs之指數，如式W00222580化合物所定義者； RSrS氫或一或多個取代基，及Rlr為若羧基被分裂開來， 而仍然留下之胺基酸部份’或下式化合物 84364 •24- 1331916Wherein R3r, R'3r, kk, ^ and ' are indices corresponding to R3, %, &amp;, heart, R7 and Rs, as defined by the compound of formula W00222580; RSrS hydrogen or one or more substituents, and Rlr If the carboxyl group is split, and still leaves the amino acid moiety' or the compound 84364 • 24-1331916

I.-W00222580 ^ 其中R3s、R，3S、R4S、、r7s及r8s個別為相應於R3、R，3、心 、R6、R7及RS之指數，如關於式〖·彻啦細化合物所定義者 ;R5s為氫或-或多個取代I ’較佳為氫；及Ris為 分裂開來」而仍然留下之胺基酸部份；例如，其中在式^化 合物中’刚原子連接至六氮咐咬環之基團係心呈 (S)-組態或呈（R)-组態；例如，其中， … 成甘、、# ^ 在基團中’胺基酸 殘基孓胺基係揲論是呈（s)_組態或呈讲)_組熊。 再者，吾人已發現新穎截短侧耳素，兑 抵抗結核分枝桿菌之活性。 ' 〜不“田菌活性與 於另一方面，本發明係提供截短 式化合物 耳素，其係選自包括下I.-W00222580 ^ wherein R3s, R, 3S, R4S, r7s and r8s are each an index corresponding to R3, R, 3, heart, R6, R7 and RS, as defined by the formula R5s is hydrogen or - or a plurality of substituents I' is preferably hydrogen; and Ris is a splitting of the amino acid moiety remaining; for example, wherein in the compound of formula ^ 'a rigid atom is attached to the hexa-nitrogen The group of the bite ring is in the (S)-configuration or in the (R)-configuration; for example, where ... is 甘,, # ^ in the group 'amino acid residue 孓 基 基 揲On the presentation of (s) _ configuration or presentation) _ group bear. Furthermore, we have discovered novel pleuromutilin, which is resistant to the activity of M. tuberculosis. '~Non' field activity and in another aspect, the present invention provides a truncated compound otoxin selected from the group consisting of

CH3〇HCH3〇H

或R,Or R,

•CH3〇h εχ Λ·~--ί•CH3〇h εχ Λ·~--ί

其中RE X係如表1中所列示者。在表^、 〇 F 合物係具有式IEX，惟實例12除外，其 貫例中，此 。所描述及根據例如類似如鲁7 i 化合物係具有 如貫例中所述之古、 &lt;万去所獲得 84364 •25 1331916 合物，其1H-NMR數據亦顯示於表1中： 表1 實例1Wherein RE X is as listed in Table 1. In the table ^, 〇 F compound has the formula IEX, except for the example 12, in this example, this. The 1H-NMR data are also shown in Table 1 as described and according to, for example, a similar compound as the Ru 7 i compound, as shown in the example, and the 1H-NMR data are also shown in Table 1: Table 1 Example 1

RexRex

14-0-【4-胺基-環己小基-硫基)_乙醯基截短 素，呈鹽酸鹽形式 (d6-DMSO): 7.9(1)，311，：^3)，/^-系統〇八=3.23, = 3.29, 2H, H2 2, J=15.2Hz), 3.03 (m, 1H, SCH), 3.10 (m, 1H, CHN)_ 實例2 14-0[(2-(R*)-((R)-组胺醯基)-胺基-環己 _i_(s*&gt; 基)-硫基乙酼基)]-截短素，呈鹽酸里形式 (d6 -DMSO):非對映異構物：8·4,9.0 (2xm，2H， NH)，7.5, 8.7 (2xb，2H,咪峻）,6.15, 5.1 (2xm，Η] 9， H2 〇, H2 !), 5.52 (d, 1H, J=5.2Hz, H14), 4.2 (m, 1H, a-H-組胺酸），3.45 (m, 1H，H!〗），3_3 (m, 2H, H2 2 )， 2.7 (m，1H，CHS)，1·18, 1·45 (2xs，（CH3L 5，（013)! 8) ，0.75, 0.88 (2xd，（CH3 6，(CH3)! 7，J=5.4Hz) 實例3a14_CH(2-(R*)-曱胺基-環己-1-(S*)-基)-硫基乙 醯基)】-截短素 (d6-DMSO):非對映異構物：6.15, 5.1 (2xm, A 9，H2 〇，H2 2 )，5.52 (d，1H，J=5.2Hz，① 4 )，4.50 (d， 1H, OH, J=5Hz), 3.45 (t, 1H, ^ ^, J=5Hz), 3.25 (m, 2H, H2 2), 3.25 (m, 1H, CHN), 2.82 (m, 1H, CHS), 2.38 (d, 3H, CH3NH, J=5.1Hz), 1.3, 1.34) 1.18, 1.45 (2xs9 (CH3)! 5, (CH3)! 8), 0.75, 0.88 (2xd, (CH3 )j 6, (CH3)17, J=5.4Hz). 實例3b 14_0-[(2-(R*)-甲胺基環己基）硫基乙 醯基)】-截短素 (d6-DMSO):非對映異構物：6.15, 5.1 (2xm，14-0-[4-Amino-cyclohexyl-thio)-acetamidin truncated as hydrochloride (d6-DMSO): 7.9(1), 311,:^3), / ^-System〇8=3.23, = 3.29, 2H, H2 2, J=15.2Hz), 3.03 (m, 1H, SCH), 3.10 (m, 1H, CHN)_ Example 2 14-0[(2-( R*)-((R)-histamine-yl)-amino-cyclohexyl-i_(s*&gt;yl)-thioethenyl)]- truncated, in the form of hydrochloric acid (d6-DMSO) ): diastereomers: 8·4, 9.0 (2xm, 2H, NH), 7.5, 8.7 (2xb, 2H, Mi Jun), 6.15, 5.1 (2xm, Η] 9, H2 〇, H2 !) , 5.52 (d, 1H, J=5.2Hz, H14), 4.2 (m, 1H, aH-histidine), 3.45 (m, 1H, H!), 3_3 (m, 2H, H2 2 ), 2.7 (m, 1H, CHS), 1·18, 1·45 (2xs, (CH3L 5, (013)! 8), 0.75, 0.88 (2xd, (CH3 6, (CH3)! 7, J=5.4Hz) Example 3a14_CH(2-(R*)-nonylamino-cyclohexan-1-(S*)-yl)-thioethenyl)]- truncated (d6-DMSO): diastereomer : 6.15, 5.1 (2xm, A 9, H2 〇, H2 2 ), 5.52 (d, 1H, J = 5.2 Hz, 1 4 ), 4.50 (d, 1H, OH, J = 5 Hz), 3.45 (t, 1H) , ^ ^, J=5Hz), 3.25 (m, 2H, H2 2), 3.25 (m, 1H, CHN), 2.82 (m, 1H, CHS), 2.38 (d, 3H, CH3NH, J=5.1Hz ), 1.3, 1.34) 1.18, 1.45 (2xs9 (CH3)! 5, (CH3)! 8), 0.75, 0.88 (2xd, (CH3)j 6, (CH3)17, J=5.4Hz). Example 3b 14_0 -[(2-(R*)-Methylaminocyclohexyl)thioethenyl)]-Termin (d6-DMSO): diastereomer: 6.15, 5.1 (2xm,

84364 -26- 1331916 H! 9, H2 〇, H2!), 5.52 (d, 1H, J=5.2Hz, ^ 4), 4.50 (d, 1H, OH, J=5Hz), 3.45 (t, 1H, Ηχ 2, J=5Hz), 3.25 (m, 2H, H22), 3.25 (m, 1H, CHN), 2.65 (m, 1H, CHS), 2.43 (d, 3H, CH3NH, J=5.1Hz), 1.3, 1.34) 1.18, 1.45 (2xs, (CH3)! 5, (CH3)! 8,0.75, 0.88 (2xd, (CH3)! 6, (CH3)17,J=5.4Hz) rex 實例4 (14-0-[4-((R)_異纈草胺醯基-胺基-環己烷-1- HN^^CH / 3 基)-硫基）乙醯基】-截短素，呈鹽酸鹽形式 nh2 (CD3 OD) ： 8.3 (d, 1H, NH), 8.1 (b, 3H, NH3), 6.15 (m, 1H, H19), 5.55 (d, 1H, H14), 5.05 (m, 2H, H20), 3.75 (m, 1H, NCHCO), 3.3 (m, 1H, NCH), 3.42 (d, 1H, HI 1), 3.25 (m, 2H, SCH2 CO), 2.98 (m, 1H, CHS), 0.9 (d, 6H, (CH3 )2 CH), 1.08, 1.36 (2xs, 6H, (CH3 )i 8, (CH3 )i 5), 0.65, 0.83 (2xd, 6H, (CH3), 6, (CH3 7) Rex 實例5a 14_0-[((3-(R*)-胺基-環庚基)硫基）乙醯 基】-截短素與14-0-[((3-(S*)-胺基-環庚-1(S*)_ 基)-硫基)-乙醯基】截短素，呈鹽酸鹽形式 NH2 (非對映異構混合物） (d6-DMSO) ： 8.0 (b,3H,NH3 + ), 6.15, 5.1 (2xm, Hi 9, H2 〇, H2!), 5.52 (d, 1H, J=5.2Hz, 4), 3.1, 3.2 (2xm, 1H, CHNH3 + ), 3.4 (m, 1H, H! t), 3.3 (m, 2H, H22), 2.9 (m, 1H，SCH), 1.18,1.45 (2xs, (CH3L 5， (CH3)! 8 ), 0.9 (m, 6H, CH(CH3 )2), 0.75, 0.88 (2xd, (CH3)16，(CH3)17，J=5_4Hz) 實例5b 14-0-[((3-(R*)-胺基-環庚-1(S*)-基）硫基）乙醯 基】-截短素與14-0-[((3-(S*)-胺基-環庚 基)硫基）乙醯基]-截短素，呈鹽酸鹽形式（ 非對映異構混合物） (d6-DMSO) ： 7.8 (b, 3H,NH3 + ), 6.15,5.1 (2xm, 84364 -27- 133191684364 -26- 1331916 H! 9, H2 〇, H2!), 5.52 (d, 1H, J=5.2Hz, ^ 4), 4.50 (d, 1H, OH, J=5Hz), 3.45 (t, 1H, Ηχ 2, J=5Hz), 3.25 (m, 2H, H22), 3.25 (m, 1H, CHN), 2.65 (m, 1H, CHS), 2.43 (d, 3H, CH3NH, J=5.1Hz), 1.3 , 1.34) 1.18, 1.45 (2xs, (CH3)! 5, (CH3)! 8,0.75, 0.88 (2xd, (CH3)! 6, (CH3)17,J=5.4Hz) rex Example 4 (14-0 -[4-((R)_isosaurinyl-amino-cyclohexane-1-HN^^CH / 3 yl)-thio)ethinyl]- truncated, hydrochloride Form nh2 (CD3 OD): 8.3 (d, 1H, NH), 8.1 (b, 3H, NH3), 6.15 (m, 1H, H19), 5.55 (d, 1H, H14), 5.05 (m, 2H, H20) ), 3.75 (m, 1H, NCHCO), 3.3 (m, 1H, NCH), 3.42 (d, 1H, HI 1), 3.25 (m, 2H, SCH2 CO), 2.98 (m, 1H, CHS), 0.9 (d, 6H, (CH3)2 CH), 1.08, 1.36 (2xs, 6H, (CH3)i 8, (CH3 )i 5), 0.65, 0.83 (2xd, 6H, (CH3), 6, (CH3 7 Rex Example 5a 14_0-[((3-(R*)-Amino-cycloheptyl)thio)ethinyl]-truncated with 14-0-[((3-(S*)-amine) Base-cyclohepta-1(S*)-yl)-thio)-ethenyl] truncation, in the form of the hydrochloride salt NH2 (diastereomeric mixture) (d6-DMSO): 8.0 (b, 3H, NH3 + ), 6.15, 5.1 (2xm, Hi 9, H2 〇, H2!), 5.52 (d, 1H, J=5.2Hz, 4), 3.1, 3.2 (2xm, 1H, CHNH3 + ), 3.4 (m, 1H, H! t) , ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( , 0.88 (2xd, (CH3)16, (CH3)17, J=5_4Hz) Example 5b 14-0-[((3-(R*)-Amino-cyclohept-1(S*)-yl)sulfide Ethyl)-tertidin and 14-0-[((3-(S*)-amino-cycloheptyl)thio)ethinyl]- truncated as a hydrochloride salt Diastereomeric mixture) (d6-DMSO): 7.8 (b, 3H, NH3 + ), 6.15, 5.1 (2xm, 84364 -27- 1331916

Hi 9, H2 〇, H2!), 5.52 (d, 1H, J=5.2Hz, Η2 4), 3.15 (2xm, 1H, CHNH3 +), 3.4 (m, 1H, t), 3.3 (m, 2H, H22), 2.95 (111, 1H, SCH), 1.18,1.45 (2xs, (CH3)15, (CH3)! 8), 0.9 (m, 6H, CH(CH3 )2,0.75, 0.88 (2xd, (CH3)16,(CH3)17,J=5.4Hz) 實例6 14-0-[(3-(R/S)-(R)-異纈草胺醯基胺基-1-(R/S)-基)硫基）乙醯基】截短素，呈鹽酸鹽形式 (d6 -DMSO) ： 8.4 (m, 1H, NHC=0), 8.1 (b, 3H, NH3 + )，6.15, 5.1 (2xm，氏 9，H2。，H2 ! )，5.52 (d, 1氏 J=5.2Hz，氏 4 )，3.5,3·9 (2x11^ 1H，a-H-異纈草胺醯 - 基），3_15 (2xm, 1H，CHNH3 + )，3.4 (m，1H，Η!! )，3.3 (m, 2H, H22), 2.95 (m, 1H, SCH), 1.18, 1.45 (2xs, (CH3)15, (CH3)! 8), 0.9 (m, 6H, CH(CH3 )2), 0.75, _0.88 (2xd, (CH3 6, (CH3 7, J=5.4Hz)_ Rax 實例7 14-0-[(3-(R/S)-胍基-環己-1-(R/S)-基)-乙醯基】 截短素-鹽酸鹽 (d6 -DMSO) ： 6.8-7.4 (b, 3H, NH3 +), 7.65,7.7 (2xm, 1H, NH), 6.15, 5.1 (2xm, Η! 9, H2〇, H21), 5.52 (d9 1H, J=5.2Hz, H! 4), 4.5 (d, 1H, OH, J=6Hz), 3.1 (m, 1H, CHNH), 3.4 (t, 1H, Hx l, J=6Hz), 3.3 (m, 2H, H22), 2.7 (m, 1H, SCH), 1.18, 1.45 (2xs, (CH3)! 5, (CH3)! 8), 0.75, 0.88 (2xd, (CH3 ), 6, (CH3 h 7, J=5.4Hz) _Hi 9, H2 〇, H2!), 5.52 (d, 1H, J=5.2Hz, Η2 4), 3.15 (2xm, 1H, CHNH3 +), 3.4 (m, 1H, t), 3.3 (m, 2H, H22), 2.95 (111, 1H, SCH), 1.18, 1.45 (2xs, (CH3)15, (CH3)! 8), 0.9 (m, 6H, CH(CH3)2, 0.75, 0.88 (2xd, (CH3) , 16, (CH3) 17, J = 5.4 Hz) Example 6 14-0-[(3-(R/S)-(R)-isosaurinylamino-1-(R/S)- Thiol)ethylidene] truncated, in the form of hydrochloride (d6-DMSO): 8.4 (m, 1H, NHC=0), 8.1 (b, 3H, NH3 + ), 6.15, 5.1 (2xm , 9, H2., H2 ! ), 5.52 (d, 1 J = 5.2 Hz, 4), 3.5, 3·9 (2x11^1H, aH-isochlorinamide-based), 3_15 (2xm) , 1H, CHNH3 + ), 3.4 (m, 1H, Η!! ), 3.3 (m, 2H, H22), 2.95 (m, 1H, SCH), 1.18, 1.45 (2xs, (CH3)15, (CH3) 8), 0.9 (m, 6H, CH(CH3)2), 0.75, _0.88 (2xd, (CH3 6, (CH3 7, J=5.4Hz)_ Rax Example 7 14-0-[(3- (R/S)-fluorenyl-cyclohexan-1-(R/S)-yl)-ethenyl] truncated-hydrochloride (d6-DMSO) : 6.8-7.4 (b, 3H, NH3 + ), 7.65,7.7 (2xm, 1H, NH), 6.15, 5.1 (2xm, Η! 9, H2〇, H21), 5.52 (d9 1H, J=5.2Hz, H! 4), 4.5 (d, 1H, OH, J=6Hz), 3.1 (m, 1H, CHNH), 3.4 (t, 1H, Hx l, J=6Hz), 3.3 (m, 2H, H22), 2.7 (m, 1H, SCH), 1.18, 1.45 (2xs, (CH3)! 5, (CH3)! 8), 0.75, 0.88 (2xd, (CH3 ), 6, (CH3 h 7, J=5.4Hz) _

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CH 3 實例8a 14-0-[3-(R*)-((R)-異纈草胺醯基-胺基-環戊-1· (S*)-基)-硫基)-乙醯基]-截短素，呈鹽酸鹽 形式 (DMSO-d6) ： 8.5 (d, 1H, NH, J=7.2Hz), 8.1 (bs, 3H, NH3 + )，6_15, 5.06, 5.02 (3xm，9，H2 〇，H2 j )，5.55 (d，1H，呒 4，J=8.2Hz), 4.05 (m，1H，H- a-異纈草胺 84364 -28- 1331916 84364 醯基）,3·15 (m，1Η，Η-Γ)，3.2-3.5 (MH-3，，％ !， H2 2), 1.35,1.05 (2xs, (CH35, (CH38 )s 0.91, 0.88 (d，(CH3 )2 CH，J=6.8Hz)，0.8, 0.62 (2xd，(CH3)! 6， (CH3)17, J=6.8Hz) 實例8b 14-0-[3-(S*)-((R)-異纈草胺醯基-胺基-環戊-1· (R*)-基）-硫基)-乙醯基】-截短素，呈鹽酸鹽 形式 (DMSO-d6) ： 8.5 (d, 1H, NH, J=7.2Hz), 8.1 (bs, 3H, NH3 + )，6.15, 5.06, 5.02 (3xm，^ 9，H2 〇，H2 i )，5·55 (d，1H，H! 4，J=8.2Hz)，4.05 (m, 1H, HD異纈草胺 醯基），3·15 (m，1H，Η-Γ)，3.2-3.5 (m，H3，，i， H2 2 )，1.35,1.05 (2xs，（CH3 h 5，（CH3)! 8 )，0.91，0.89 (d, (CH3 )2 CH, J=6.9Hz), 0.8, 0.62 (2xd, (CH3 )j 6, (CH3)17, J=6.8Hz). 實例8c 14-0-[3-(S*)-((R)-異纈草胺醯基-胺基-環戊-1-(S*)-基)-硫基)_乙醯基】-截短素與14-0-[3-体*)_ ((R)_異纈草胺醯基-胺基-環戊基）-‘ 基)·乙醯基】-截短素，呈鹽酸鹽形式（反式 非對映異構物之混合物） (DMSO-d6) ： 8.52, 8.53 (2xd, 1H, NH, J=6.9Hz), 8.1 (bs, 3H, NH3 + ), 6.15,6.12,5.0-5.1 (6xm, H19, H2 〇, H2!), 5.54, 5.55 (2xd, 1H, Hi 4, J=8.2Hz), 4.15 (m，1H，HD異纈草胺醯基），3.1-3.5 (m，Η-Γ， H3’，^ i，H2 2 )，1.35, 1.05 (2xs, (CH3 久 5，（CH3)! 8 )， 0.91,0.88 (d, (CH3 )2 CH, J=6.8Hz), 0.8,0.62 (2xd, (CH3)16,(CH3)17&gt;J=6.8Hz) -29·CH 3 Example 8a 14-0-[3-(R*)-((R)-isosporin-yl-amino-cyclopentyl-1·(S*)-yl)-thio)-acetamidine Base]- truncated, in the form of the hydrochloride (DMSO-d6): 8.5 (d, 1H, NH, J = 7.2 Hz), 8.1 (bs, 3H, NH3 + ), 6_15, 5.06, 5.02 (3xm, 9, H2 〇, H2 j ), 5.55 (d, 1H, 呒 4, J = 8.2 Hz), 4.05 (m, 1H, H-a-isochloramide 84364 -28- 1331916 84364 醯 base), 3· 15 (m,1Η,Η-Γ), 3.2-3.5 (MH-3,,% !, H2 2), 1.35,1.05 (2xs, (CH35, (CH38 )s 0.91, 0.88 (d,(CH3 )2) CH, J = 6.8 Hz), 0.8, 0.62 (2xd, (CH3)! 6, (CH3) 17, J = 6.8 Hz) Example 8b 14-0-[3-(S*)-((R)- Valeric acid-amino-cyclopenta-1(R*)-yl)-thio)-ethenyl]- truncated as hydrochloride (DMSO-d6): 8.5 (d, 1H, NH, J=7.2Hz), 8.1 (bs, 3H, NH3 + ), 6.15, 5.06, 5.02 (3xm, ^ 9, H2 〇, H2 i ), 5·55 (d, 1H, H! 4, J=8.2Hz), 4.05 (m, 1H, HD isoammine oxime), 3·15 (m, 1H, Η-Γ), 3.2-3.5 (m, H3,, i, H2 2 ), 1.35 , 1.05 (2xs, (CH3 h 5, (CH3)! 8 ), 0.91, 0.89 (d, (CH3 ) 2 CH, J = 6.9 Hz), 0.8, 0.62 (2xd, (CH3 )j 6, (CH3)17, J=6.8Hz). Example 8c 14-0-[3-(S*)-((R)-isoindolizinyl-amino-cyclopentan-1-(S* )-yl)-thio)-ethinyl]- truncated and 14-0-[3-body*)_((R)-isosporin-yl-amino-cyclopentyl)-' Base)·Ethyl]- truncated, in the form of the hydrochloride (mixture of trans diastereomers) (DMSO-d6): 8.52, 8.53 (2xd, 1H, NH, J=6.9Hz) , 8.1 (bs, 3H, NH3 + ), 6.15, 6.12, 5.0-5.1 (6xm, H19, H2 〇, H2!), 5.54, 5.55 (2xd, 1H, Hi 4, J=8.2Hz), 4.15 (m , 1H, HD isoxachlorinyl), 3.1-3.5 (m, Η-Γ, H3', ^ i, H2 2 ), 1.35, 1.05 (2xs, (CH3 long 5, (CH3)! 8 ), 0.91, 0.88 (d, (CH3)2 CH, J=6.8Hz), 0.8, 0.62 (2xd, (CH3)16, (CH3)17> J=6.8Hz) -29·

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HN、/NH2 T NH 實例914-0-【((3-(R/S)-胺基-環戊基)-硫基)-乙醯基】-截短素-里酸鹽 (DMSO-d6) ： 8.03 (bs, 3H,NH3 + ), 6.13, 5.05 (2xm, 3H，H19，H2〇，H21)，5.55(d，lH,H14，J=8.0Hz)，3.2-3.6 (m, H-3', H! t, H22), 3.14 (m, 1H, H14), 1.35,1.05 (2xs, (CH3 ^ 5, (CH3 )2 8), 0.8, 0.62 (2xd, (CH3 h 6，(CH3 h 7，J=6.8Hz)_ 實例10 14-0-[(2-(R*M(R)-異纈草胺醯基)-曱胺基-辕 己基)-硫基乙醯基)】截短素，呈鹽 酸鹽形式 (d6 -DMSO):非對映異構物：8.0 (m，3H，NH3 + )， 6.15,5.1 (2xm，H19，H20，H21)，5.52(d，1H，J= 5.2Hz，氏 4 )，4.50 (m，1H，OH)，4.2 (m，1H，a-H-纈胺 酸），3.45 (m，1H，&amp; 丨），3.25 (m，2H，H2 2 )，3.25,（m， 1H, CHN), 2.82 (m, 1H, CHS), 2.88, 2.94 (2xs, 3H, CH3N), 1.3, 1.34)，1.18, 1.45 (2xs，(CH3)15，(CH3)18) ，0.75, 0.88，(2xd，（CH3 h 6，（CH3 )! 7，J=5.4Hz) 實例1114-〇-[(3-胍基-苯基硫基)-乙醯基]截短素， 呈鹽酸鹽形式 (CDC13) ： 0.58 (d, 3H, Hj 6, J=7.2Hz), 0.81 (d, 3H, 7，J=7.3Hz)，1.02 (s，3H，8 )，1.32 (s, 3H,氏 5 )， ABX-系統（i^a=1.2，Η131)，】= 16.1Hz, J=9.1Hz), 2.08 (d, 1H, H4, J=2.1Hz), ABXY-系統（Va=2.23, VB=2-19，H2a，H2b，J=16.2Hz，J= 9.1Hz，J=1.8Hz)，2.3 (m，1H，H! 〇)，3.4 (d，1H，％ i，J= 5.98Hz), AB-系統（1/*α=3·81，Vb=3.89,2H，H22， J=14.1Hz), 5.18 (dd, lH,H20a, J=17.5Hz, J=1.6Hz), 5.29 (dd, 1H, H20b5 J=11HZ) J=l.6Hz), 5.51 (d, 1H, 84364 -30- 1331916HN, /NH2 T NH Example 914-0-[(3-(R/S)-Amino-cyclopentyl)-thio)-ethenyl]- truncated-lithium salt (DMSO-d6) ) : 8.03 (bs, 3H, NH3 + ), 6.13, 5.05 (2xm, 3H, H19, H2〇, H21), 5.55 (d, lH, H14, J=8.0Hz), 3.2-3.6 (m, H- 3', H! t, H22), 3.14 (m, 1H, H14), 1.35, 1.05 (2xs, (CH3 ^ 5, (CH3 )2 8), 0.8, 0.62 (2xd, (CH3 h 6, (CH3) h 7,J=6.8Hz)_ Example 10 14-0-[(2-(R*M(R)-isoinvalidyl)-nonylamino-hexyl)-thioethenyl)] Truncated, in the form of the hydrochloride (d6-DMSO): diastereomer: 8.0 (m, 3H, NH3 + ), 6.15, 5.1 (2xm, H19, H20, H21), 5.52 (d, 1H) , J = 5.2 Hz, 4), 4.50 (m, 1H, OH), 4.2 (m, 1H, aH-proline), 3.45 (m, 1H, &amp; 丨), 3.25 (m, 2H, H2) 2), 3.25, (m, 1H, CHN), 2.82 (m, 1H, CHS), 2.88, 2.94 (2xs, 3H, CH3N), 1.3, 1.34), 1.18, 1.45 (2xs, (CH3)15, ( CH3) 18), 0.75, 0.88, (2xd, (CH3 h 6, (CH3)! 7, J = 5.4 Hz) Example 1114-〇-[(3-indolyl-phenylthio)-ethenyl] Truncated, in the form of the hydrochloride (CDC13): 0.58 (d, 3H, Hj 6, J = 7.2 Hz), 0 .81 (d, 3H, 7, J = 7.3 Hz), 1.02 (s, 3H, 8), 1.32 (s, 3H, 5), ABX-system (i^a=1.2, Η131),] = 16.1 Hz, J=9.1Hz), 2.08 (d, 1H, H4, J=2.1Hz), ABXY-system (Va=2.23, VB=2-19, H2a, H2b, J=16.2Hz, J= 9.1Hz, J=1.8Hz), 2.3 (m,1H,H! 〇), 3.4 (d,1H,% i,J= 5.98Hz), AB-system (1/*α=3·81, Vb=3.89, 2H , H22, J=14.1Hz), 5.18 (dd, lH, H20a, J=17.5Hz, J=1.6Hz), 5.29 (dd, 1H, H20b5 J=11HZ) J=l.6Hz), 5.51 (d, 1H, 84364 -30- 1331916

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H2 4, J=8.3Hz), 6.05 (dd, 1H, Hj 9, J=llHz, J=17.5 Hz), 7·0 (m，1H，芳族 H)，7.18 (m，2H，芳族 H), 7.3t, 1H，芳族 H5，J=8Hz _ 實例12 14-0-[(N-(3-甲基-2(R)-胺基-丁醯基)-六氫吡 啶-3(S)-基)-硫基乙醯基]_2(S)_氟-截短素，呈 鹽酸鹽形式 (DMSO-d6):旋轉異構物：7.95(bs，3H,NH3 + )， 6.12, 5.05 (2xm, Hi 9, H2 〇, H2 }), 5.56, 5.52 (2xd, 1H, Hj 4, J=8.3Hz), 4.92 (ddd, 1H, H2, J=51.3, 8.4, 8.0Hz) ,4.7,4.69 (2xd, 1H, 11-OH, J=6.1Hz), 4.06 (m, 1H, HQ異纈草胺醯基）,4.3,4.25, 3.91，3.88,2.6-3,6 (m, 4xCH2N, SCH, Hj t, H22), 1.39, 1.06 (2xs, (CH3)! 5, (CH3 )i 8), 0.99, 0.9, 0.84, 0.64 (4xd, (CH3 )2 CH, (CH3), 6, (CH3 )t 7, J=6.8Hz)_ 實例1314-0-[((六氫吡啶-3⑶-基）甲基-硫基）-乙醯基 】-截短素，呈鹽酸鹽形式 (d6 -DMSO, 350K): 6.15, 5.05 (2xm，&amp; 9，H2 〇，H2 i )， 5.55 (d，1H，5,2Hz，叫 4 )，3.4 (d, 1H，氏 i，J=5.2Hz)， 3.05, 2.95, 2.52, 2.31，2.09, (5xm, 4H，CH2NCH2)， 3.2 (m，2H，SCH2 C=0)，2.48 (m，2H，CHCH2 S)，1.18, 1.45 (2xs, (CH3)! 5, (CH3)! 8), 0.75, 0.88,(2xd5 (CH3)16,(CH3)17,J=5.4Hz)_ 實例1414-0-[((—氮七園烷-4-(R/S)-基)-硫基乙醯基 )】-截短素，呈鹽酸鹽形式 400 毫克 14-0-[((N-B0C—氮七圜烷-4-(R/S)-基 )-硫基乙醯基）-截短素（d6-DMSO) : 8.2-8.5 (b， 2H, NH2 +), 6.15, 5.1 (2xm, Η! 9, H2 〇, H2 j), 5.52 (d, 1H, J=5.2Hz, Hj 4), 4.52 (d, 1H, OH, J=6.2Hz) 3.4 (t, 1H, H!!, J=6.2Hz), 3.3 (m, 2H, H22), 2.9-3.2 (2xm, 84364 -31 - 1331916H2 4, J=8.3Hz), 6.05 (dd, 1H, Hj 9, J=llHz, J=17.5 Hz), 7·0 (m, 1H, aromatic H), 7.18 (m, 2H, aromatic H ), 7.3t, 1H, aromatic H5, J=8Hz _ Example 12 14-0-[(N-(3-methyl-2(R)-Amino-butanyl)-hexahydropyridine-3(S) -yl)-thioethenyl]_2(S)-fluoro- truncated as hydrochloride (DMSO-d6): rotamer: 7.95 (bs, 3H, NH3 + ), 6.12, 5.05 (2xm, Hi 9, H2 〇, H2 }), 5.56, 5.52 (2xd, 1H, Hj 4, J=8.3Hz), 4.92 (ddd, 1H, H2, J=51.3, 8.4, 8.0Hz), 4.7, 4.69 (2xd, 1H, 11-OH, J=6.1Hz), 4.06 (m, 1H, HQ isoxachlorinyl), 4.3, 4.25, 3.91, 3.88, 2.6-3, 6 (m, 4xCH2N, SCH , Hj t, H22), 1.39, 1.06 (2xs, (CH3)! 5, (CH3 )i 8), 0.99, 0.9, 0.84, 0.64 (4xd, (CH3 )2 CH, (CH3), 6, (CH3 ) t 7, J = 6.8 Hz) _ Example 1314-0-[((hexahydropyridine-3(3)-yl)methyl-thio)-ethenyl]- truncated, in the form of the hydrochloride salt (d6 - DMSO, 350K): 6.15, 5.05 (2xm, &amp; 9, H2 〇, H2 i ), 5.55 (d, 1H, 5, 2Hz, called 4), 3.4 (d, 1H, i, J = 5.2Hz) , 3.05, 2.95, 2.52, 2.31, 2.09, (5xm, 4H, CH2NCH2), 3.2 (m, 2H, SCH2 C=0), 2.48 (m, 2H, CHCH2 S), 1.18, 1.45 (2xs, (CH3)! 5, (CH3)! 8), 0.75, 0.88, (2xd5 (CH3)16, (CH3)17, J=5.4Hz)_ Example 1414-0-[((--N-octadecane-4-(R/S)-yl)-thioethenyl)]- truncation, in the form of the hydrochloride salt 400 mg 14-0-[( (N-B0C-azopentane-4-(R/S)-yl)-thioethenyl)- truncated (d6-DMSO) : 8.2-8.5 (b, 2H, NH2 +), 6.15 , 5.1 (2xm, Η! 9, H2 〇, H2 j), 5.52 (d, 1H, J=5.2Hz, Hj 4), 4.52 (d, 1H, OH, J=6.2Hz) 3.4 (t, 1H, H!!, J=6.2Hz), 3.3 (m, 2H, H22), 2.9-3.2 (2xm, 84364 -31 - 1331916

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〇 3H, SCH, CHNCH), 1.18, 1.45 (2xs, (CH3 )2 5, (CH3 8 )，0.75,0.88 (2xd，（CH3 h 6，（CH3 7，J=- 5.4Hz_ 實例1514-0-丨((N-(R)-異纈草胺醯基一氮七園烷-4-(R/S)-基)-硫基乙醯基)】-截短素-鹽酸鹽 (d6-DMSO) ： 7.7-8.0 (b, 3H, NH3 + ), 6.15, 5.1 (2xm, Hi 9, H2 〇, H21), 5.52 (d, 1H, J=5.2Hz, 4 ), 4.52 (d, 1H, OH, J=6.2Hz), 3.4 (t, 1H, Hj {, J=6.2Hz), 4.1 (m, α-H-纈胺酸），3.4, 2.6 (2xm, 4H, CH2NCH2) 3.3. (m, 2H, H22), 2.9 (m, 1H, SCH), 1.18, 1.45 (2xs, (CH3), 5, (CH3 )x 8 ), 0.75, 0.88 (2xd, (CH3), 6, (CH3)17, J=5.4Hz)_ 實例1614-0-[(N-(R)-異纈草胺醯基-四氫吡咯-3(S)-基 )-硫基-乙醯基]-截短素-鹽酸鹽 (CD3 OD):旋轉異構物 8.1 (b, 3H，NH3), 6.3-6.4 (m, 1H, H19), 5.75 (d, 1H, H14), 5.15 (m, 2H, H20&gt;, 4.15 (m, 1H, NCHCO), 3.9 (m, 1H, NCH), 3.6 (m, 1H, NCH), 3.42 (d, 1H, Hll), 3.28-3.35 (m, 2H, SCH2 CO), 0.95, 0.98 (2xd, 6H, (CH3 )2 CH), 1.08, 1.36 (2xs, 6H, (CH3 8, (CH3 5), 0.65, 0.83 (2xd, 6H，(CH3)16，(CH3)17)_ 實例17 14-0-[((N-(R)-六氫吡啶甲醯基-六氫吡啶-4-基）甲基-硫基）-乙醯基】-截短素，呈鹽酸鹽 形式 1H-NMR (d6 -DMSO, 350K) ： 6.15,5.05 (2xm, Hj 9, H2 〇, H2!), 5.55 (d, 1H, 5,2Hz, H! 4 ), 3.35 (d, 1H, 4 丨，J=5.2Hz), 4.3 (m, α-H-六氫 p比咬曱酿），4.2, 4.05, 3.75 (4xm，CH2NCH2)，AB-系統：3.12,3.18, J=14.7Hz, H22), 2.8 (m, 1H, SCH), 1.18, 1.45 (2xs,〇3H, SCH, CHNCH), 1.18, 1.45 (2xs, (CH3)2 5, (CH3 8 ), 0.75, 0.88 (2xd, (CH3 h 6, (CH3 7, J=- 5.4Hz_ Instance 1514-0-丨((N-(R)-Isoamylamine-l-hep-7-carboxan-4-(R/S)-yl)-thioethenyl)]-truncated-hydrochloride (d6- DMSO) : 7.7-8.0 (b, 3H, NH3 + ), 6.15, 5.1 (2xm, Hi 9, H2 〇, H21), 5.52 (d, 1H, J=5.2Hz, 4 ), 4.52 (d, 1H, OH, J=6.2Hz), 3.4 (t, 1H, Hj {, J=6.2Hz), 4.1 (m, α-H-proline), 3.4, 2.6 (2xm, 4H, CH2NCH2) 3.3. (m , 2H, H22), 2.9 (m, 1H, SCH), 1.18, 1.45 (2xs, (CH3), 5, (CH3)x 8 ), 0.75, 0.88 (2xd, (CH3), 6, (CH3)17 , J=5.4Hz)_ Example 1614-0-[(N-(R)-isosastinalinyl-tetrahydropyrrole-3(S)-yl)-thio-ethenyl]- truncated - hydrochloride (CD3 OD): rotamer 8.1 (b, 3H, NH3), 6.3-6.4 (m, 1H, H19), 5.75 (d, 1H, H14), 5.15 (m, 2H, H20) , 4.15 (m, 1H, NCHCO), 3.9 (m, 1H, NCH), 3.6 (m, 1H, NCH), 3.42 (d, 1H, Hll), 3.28-3.35 (m, 2H, SCH2 CO), 0.95 , 0.98 (2xd, 6H, (CH3 )2 CH), 1.08, 1.36 (2xs, 6H, (CH3 8, (CH3 5), 0.65, 0.83 (2xd, 6H,(CH3)16,(CH3)17)_ Example 17 14-0- [((N-(R)-hexahydropyridinyl-hexahydropyridin-4-yl)methyl-thio)-ethinyl]- truncated as a hydrochloride salt 1H-NMR (d6 -DMSO, 350K) : 6.15,5.05 (2xm, Hj 9, H2 〇, H2!), 5.55 (d, 1H, 5,2Hz, H! 4 ), 3.35 (d, 1H, 4 丨, J=5.2Hz ), 4.3 (m, α-H-hexahydrop than bite), 4.2, 4.05, 3.75 (4xm, CH2NCH2), AB-system: 3.12, 3.18, J=14.7Hz, H22), 2.8 (m, 1H, SCH), 1.18, 1.45 (2xs,

84364 -32- 1331916 (CH3)! 5, (CH3)! 8), 0.75, 0.88 (2xd, (CH3){6, _(CH3 )λ 7, J=5.4Hz)__ 於另一方面，本發明係提供下式化合物84364 -32- 1331916 (CH3)! 5, (CH3)! 8), 0.75, 0.88 (2xd, (CH3){6, _(CH3)λ 7, J=5.4Hz)__ In another aspect, the invention Providing a compound of the formula

-虛線為一個鍵結（雙鍵介於位置a=b之間），Ria為氫，而R2a 不存在 戒 •虚線為無鍵結（單鍵介於位置a_b之間），且R1A與係互 相獨立為氫、函素或氘， 1^3八為（匸1-6)燒1基， R4A為氫、（A _6)院基、基團或胺基酸之殘基， Κ·5Α為氫，或 心八與RSA—起為基團，- The dotted line is a bond (double bond between positions a=b), Ria is hydrogen, and R2a is absent. • The dotted line is no bond (single bond is between positions a_b), and R1A is tied Independent of each other as hydrogen, a hydroxyl or a hydrazine, 1^3 octa ((1-6) is a base, R4A is a hydrogen, (A _6) a base, a group or an amino acid residue, Κ·5Α Hydrogen, or heart eight and RSA - as a group,

RfiA為氫或氘，及 為0、1、2、3、4或5。 在式IA化合物中，較佳情況是 ••虛線為無鍵結； -R1A為氫， -R&gt;2a為氫， 84364 -33- 1331916 -Rm為（clM)燒基，譬如甲基， _ ^4A與如上文定義， • &amp;A為氫，及 πιΑ 為 2、3 或 4 ; 例如包括截短側耳素，其係選自包括下式化合物RfiA is hydrogen or helium and is 0, 1, 2, 3, 4 or 5. In the compound of formula IA, it is preferred that the ?? dotted line is no bond; -R1A is hydrogen, -R&gt;2a is hydrogen, 84364 -33-1331916 -Rm is (clM) alkyl, such as methyl, _ ^ 4A is as defined above, • &amp;A is hydrogen, and πιΑ is 2, 3 or 4; for example, including pleuromutilin, which is selected from the group consisting of

其中REX係如表2中所列示者。所描述及根據例如類似如實 例中所述之方法所獲得之化合物，其1H-NMR數據亦顯示於 表2中： 表2 ——.Among them, REX is as listed in Table 2. The 1H-NMR data described and according to, for example, a compound obtained by a method similar to that described in the examples are also shown in Table 2: Table 2 -.

Rex % / H2N 實例18 Rex 實例18a 14-0-[(3-(R*)-胺基-1-甲基-環戊基)··硫 ΗΧ cr 基)-乙醯基】-截短素與14-〇-【(3-(S*)-胺基-1-甲 基-環戊-1-(S*)-基)-硫基)-乙醯基】-截短素’ )— h2n 呈鹽酸鹽形式（反式非對映異構物之混合 物） (DMSO-d6) ·· 7.98 (bs, 3H,NH3 + ), 6.13, 5.06, 5.03 (3xm，％ 9，H2 q，H2 1 )，5.55 (d，1H，A 4，J=8.2Hz)， 3.56 (m, 1H，H-3')，3.3-3.3 (m，!，H2 2)，1.36, 1.30， 84364 -34- 1331916 1.29,1.05 (4xs, 9H, CH3 CS, (CH3 \ 5, (CH3 \ 8), 0.8, 0.62 (2xd, (CH3)16?(CH3)17,J=6.9Hz)__Rex % / H2N Example 18 Rex Example 18a 14-0-[(3-(R*)-Amino-1-methyl-cyclopentyl)··thiol yl)-ethenyl]- truncated And 14-〇-[(3-(S*)-amino-1-methyl-cyclopentan-1-(S*)-yl)-thio)-ethinyl]- truncated') H2n is in the form of the hydrochloride salt (mixture of trans diastereomers) (DMSO-d6) ·· 7.98 (bs, 3H, NH3 + ), 6.13, 5.06, 5.03 (3xm, % 9, H2 q, H2 1), 5.55 (d, 1H, A 4, J = 8.2 Hz), 3.56 (m, 1H, H-3'), 3.3-3.3 (m, !, H2 2), 1.36, 1.30, 84364 -34- 1331916 1.29,1.05 (4xs, 9H, CH3 CS, (CH3 \ 5, (CH3 \ 8), 0.8, 0.62 (2xd, (CH3)16?(CH3)17,J=6.9Hz)__

Rex d. h2n 實例1肋 14_〇-丨(3-(R*)-胺基-1-甲基-環戊基）-硫 基)-乙醯基】-截短素與14-0-丨(3-(S*)-胺基-1甲 基-環戊基)-硫基）-乙醯基】-截短素， 呈鹽酸鹽形式（順式·非對映異構物之混合 物） (DMSO-d6) ： 8.03 (bs33H,NH3 + ), 6.13, 5.06, 5.03 (3xm, Hi 9, H2 〇, H2 1), 5.53 (d, 1H, Hj 4, J=8.0HzX 4.52 (bs, 1H-11-0H), 3.51 (m, 1H, H-3'), 3.2-3.4 (m, Hi i, H2 2), 1.41, 1.40,1.35, 1.05 (4xs, 9H, CH3CS, (CH3 h 5, (CH3 h 8), 0.8, 0.62 (2xd, (CH3 h 6, (CH3)17, J=6.9Hz) _Rex d. h2n Example 1 rib 14_〇-丨(3-(R*)-amino-1-methyl-cyclopentyl)-thio)-ethenyl]-truncated and 14-0-丨(3-(S*)-Amino-1methyl-cyclopentyl)-thio)-ethinyl]- truncated, in the form of the hydrochloride (cis-diastereomer) Mixture) (DMSO-d6): 8.03 (bs33H, NH3 + ), 6.13, 5.06, 5.03 (3xm, Hi 9, H2 〇, H2 1), 5.53 (d, 1H, Hj 4, J=8.0HzX 4.52 (bs , 1H-11-0H), 3.51 (m, 1H, H-3'), 3.2-3.4 (m, Hi i, H2 2), 1.41, 1.40, 1.35, 1.05 (4xs, 9H, CH3CS, (CH3 h 5, (CH3 h 8), 0.8, 0.62 (2xd, (CH3 h 6, (CH3)17, J=6.9Hz) _

實例19Example 19

實例19a 14-0-{[(lS*，3S*)-3-((R)-2-胺基-3-甲基-丁醯基 胺基)-1-甲基-環戊基硫基】-乙醯基}-截短素 ，呈鹽酸鹽形式 旋轉異構物 1 : (DMSO-d6) : 8.48 (d, 1H，NH, J=7.1Hz), 8.1 (bs, 3H,NH3 + )5 6.11, 5.06, 5.03 (3xm, Hi 9，H20，H2 i )，5.55 (d，1H，氏 4，J=8.5Hz)，4.15 (m， 1H，HD異纈草胺醯基），3.1-3.5 (m，Η-Γ，H-3’， Hn,H22), 1.35, 1.32, 1.05 (3xs, CH3CS, (CH3)15, (CH3)18), 0.91,0.88 (d, (CH3)2CH, J=6.8Hz), 0.8, 0.6 2 (2xd, (CH3 ), 6, (CH3 h 7, J=6.8Hz). 旋轉異構物 2 : (DMSO-d6) : 8.48 (d，1H，NH, 84364 •35- 1331916 J=7.1Hz), 8.1 (bs, 3H,NH3 + ), 6.11, 5.06, 5.03 (3xm, Hi 9, H2〇, H21), 5.55 (d, 1H, H! 4s J=8.5Hz), 4.5 (bs, 1H, 11-OH)，4.15 (m, 1H, H□異纈草胺醯基）， 3.1-3.5 (m,H-l',H-3',Hn,H22), 1.35, 1.32,1.05 (3xs, CH3 CS, (CH3 &gt;! 5, (CH3 \ 8), 0.91, 0.88 (d, (CH3 )2 CH, J=6.8Hz), 0.8,0.62 (2xd, (CH3 )λ 6, (CH3)17, J=6.8Hz) ^ . Rec 實例19b &lt;x / nh2 14-0-{[(lR*，3R*)-3-((R)-2-胺基-3-甲基-丁醯基 胺基)-1-甲基-環戊基硫基卜乙醯基}-截短素- HN、； 鹽酸里 F VcH3 (DMSO-d6):旋轉異構物：8.53 (d，1H，NH，J= H30 7.2Hz), 8.1 (bs, 3H, NH3 + ), 6.12, 5.06, 5.03 (3xm, H! 9, H2 〇, H2!), 5.55 (d, 1H, H! 4, J=8.4Hz), 4.52 (d, 1H, 11-OH，J=6.1Hz)，4.25 (m，1H，H|3異纈草胺 醯基），3.2-3.5 (m，·，H-3·，氐 i，H22)，1_42,1.39， 1.35, 1.05 (4xs, 9H, CH3 CS, (CH3 h 5, (CH3), 8), - 0.91, 0.88 (d, (CH3 )2 CH, J=6.8Hz), 0.8, 0.62 (2xd,-(CH3)165(CH3)17jJ=6.8Hz)Example 19a 14-0-{[(lS*,3S*)-3-((R)-2-Amino-3-methyl-butanylamino)-1-methyl-cyclopentylthio]- Ethyl}- truncated, in the form of the hydrochloride salt of the isomer 1 : (DMSO-d6) : 8.48 (d, 1H, NH, J = 7.1 Hz), 8.1 (bs, 3H, NH3 + )5 6.11, 5.06, 5.03 (3xm, Hi 9, H20, H2 i ), 5.55 (d, 1H, 4, J = 8.5 Hz), 4.15 (m, 1H, HD isoxachlorinyl), 3.1-3.5 (m, Η-Γ, H-3', Hn, H22), 1.35, 1.32, 1.05 (3xs, CH3CS, (CH3)15, (CH3)18), 0.91,0.88 (d, (CH3)2CH, J =6.8Hz), 0.8, 0.6 2 (2xd, (CH3), 6, (CH3 h 7, J=6.8Hz). Rotamer 2 : (DMSO-d6) : 8.48 (d,1H,NH, 84364 • 35- 1331916 J=7.1Hz), 8.1 (bs, 3H, NH3 + ), 6.11, 5.06, 5.03 (3xm, Hi 9, H2〇, H21), 5.55 (d, 1H, H! 4s J=8.5Hz ), 4.5 (bs, 1H, 11-OH), 4.15 (m, 1H, H) isoxachlorinyl), 3.1-3.5 (m, H-l', H-3', Hn, H22), 1.35, 1.32, 1.05 (3xs, CH3 CS, (CH3 &gt;! 5, (CH3 \ 8), 0.91, 0.88 (d, (CH3)2 CH, J=6.8Hz), 0.8, 0.62 (2xd, (CH3) λ 6, (CH3)17, J=6.8Hz) ^ . Rec Example 19b &lt;x / nh2 14-0-{[(lR*,3R*)-3-((R)-2-Amino- 3-methyl-butyl Hydrazinyl)-1-methyl-cyclopentylthiopyridinyl}- truncation-HN; hydrochloric acid F VcH3 (DMSO-d6): rotamer: 8.53 (d, 1H, NH, J= H30 7.2Hz), 8.1 (bs, 3H, NH3 + ), 6.12, 5.06, 5.03 (3xm, H! 9, H2 〇, H2!), 5.55 (d, 1H, H! 4, J= 8.4 Hz), 4.52 (d, 1H, 11-OH, J = 6.1 Hz), 4.25 (m, 1H, H|3 isoxachlorinyl), 3.2-3.5 (m, ·, H-3·,氐i, H22), 1_42, 1.39, 1.35, 1.05 (4xs, 9H, CH3 CS, (CH3 h 5, (CH3), 8), - 0.91, 0.88 (d, (CH3)2 CH, J=6.8Hz ), 0.8, 0.62 (2xd, -(CH3)165(CH3)17jJ=6.8Hz)

實例 19cExample 19c

14-0-{[(lR*，3S*)-3-((R)_2-胺基-3-曱基-丁醯基 胺基)-1-甲基·環戊基硫基]-乙醯基}-截短素 與 14-0-{[(lS*,3R*)-3-((R)-2·胺基-3-甲基-丁醯 基胺基)-1-甲基-環戊基硫基]-乙醯基}-截短 素，呈鹽酸鹽形式（順式非對映異構物之 混合物） (DMSO-d6) ： 8.4, 8.3 (2xd, 1H, NH, J=7.2Hz), 8.17 (bs, 3H, NH3 + )，6.12, 5.06, 5.02 (3xm, &amp; 9，H2 〇， H2!), 5.55 (d, 1H, Hi 4, J=8.3Hz), 4.53 (bs, 1H, 11-OH)，4.15 (m, 1H，HD異纈草胺醯基），3.2-3.5 (m, H-l', H-3',H11sH22), 1.36, 1.35, 1.32, 1.05 (4xs, 9H, CH3 CS5 (CH3)! 5, (CH3 8), 0.92, 0.91,0.89, 84364 -36- 133191614-0-{[(lR*,3S*)-3-((R)_2-Amino-3-indolyl-butanylamino)-1-methyl·cyclopentylthio]-ethenyl }- Truncated with 14-0-{[(lS*,3R*)-3-((R)-2·amino-3-methyl-butanylamino)-1-methyl-cyclopentyl Thio]-ethenyl}- truncated, in the form of the hydrochloride (mixture of cis diastereomers) (DMSO-d6): 8.4, 8.3 (2xd, 1H, NH, J = 7.2 Hz ), 8.17 (bs, 3H, NH3 + ), 6.12, 5.06, 5.02 (3xm, &amp; 9, H2 〇, H2!), 5.55 (d, 1H, Hi 4, J=8.3Hz), 4.53 (bs, 1H, 11-OH), 4.15 (m, 1H, HD isoxachlorinyl), 3.2-3.5 (m, H-l', H-3', H11sH22), 1.36, 1.35, 1.32, 1.05 (4xs , 9H, CH3 CS5 (CH3)! 5, (CH3 8), 0.92, 0.91, 0.89, 84364 -36- 1331916

RexRex

0.88 (2xd, 6H, (CH3 )2 CH, J=6.8Hz), 0.8,0.62 (2xd, (CH3)16,(CH3)17&gt;J=6.8Hz)_— 實例20 14-CH((3-(R/S)-胺基-環己-1-(R/S)-甲基-1-基)硫 基）乙醯基】截短素，呈鹽酸鹽形式 (d6 -DMSO):旋轉異構物：7.90 (b，3H，NH3 + )， 6.15, 5·1 (2xm，％ 9，H2 〇，H2 i )，5.52 (d，1H，J=5_2 Hz, &amp; 4 )，4.5 (2xd，1H，OH，J=6Hz)，3.4 (t，1H，印 i， J=6Hz)，3.3 (m，2H，H22)，3.1 (m，1H，NCH)，1.2， 1.25 (2xs, 3H, CH3CS)- 1.18, 1.45 (2xs, (CH3)15,. (CH3)! 8), 0.9 (m, 6H, CH(CH3 )2), 0.75, 0.88 (2xd, (CH3)16,(CH3)17,J=5.4Hz)_ 實例21a 14-0-[(3-(R*)-胍基-環己甲基-1-基）-乙 醯基】截短素，呈鹽酸鹽形式+ 14-0-[(3-(S*)· 脈'基-環己-1-(S*)-甲基-1-基)-乙酿基】截短素 ，呈鹽酸鹽形式 (d6 -DMSO) ： 10.7, 8.6, 7.65, (3xm, 2H, NH), 6.7-7.5 (b, 2H, NH), 6.15, 5.1 (2xm, Η! 9, H2 〇, H21), 5.52 (d, 1H, J=5.2Hz, H! 4), 5.5 (d, 1H, OH, J=6Hz), 3.9, 3.6 (2xm, 1H, CHNH), 3.4 (t, 1H, H:}, J=6Hz), 3.3 (m, 2H, H2 2), 1.4, 1.45 (2xs, 3H, CH3 CS), 1.18,1.45 (2xs, (CH3 h 5, (CH3)! 6), 0.75, 0.88 (2xd, (CH3), 6, (CH3)17} J=5.4Hz). 實例21b 14-0-[(3-(R*)-胍基-環己-1-(S*)-甲基-1-基）-乙 醯基】截短素，呈鹽酸鹽形式+ l4-〇-【(3-(S*)-胍基-環己甲基-1-基）乙醯基】截短素 ，呈鹽酸鹽形式 (d6 -DMSO) ： 10.7, 8.6, 7.65, (3xm, 2H, NH), 6.7-7.5 (b, 2H, NH), 6.15, 5.1 (2xm, H! 9, H2 〇, H2 !), 5.52 (d, 1H, J=5.2Hz, Hj 4), 5.5 (d, 1H, OH, J=6Hz), 3.9, 3.60.88 (2xd, 6H, (CH3)2 CH, J=6.8Hz), 0.8, 0.62 (2xd, (CH3)16, (CH3)17>J=6.8Hz)_—Example 20 14-CH((3- (R/S)-Amino-cyclohex-1-(R/S)-methyl-1-yl)thio)ethinyl] truncated, in the form of the hydrochloride (d6-DMSO): rotating Isomer: 7.90 (b, 3H, NH3 + ), 6.15, 5·1 (2xm, % 9, H2 〇, H2 i ), 5.52 (d, 1H, J=5_2 Hz, &amp; 4 ), 4.5 ( 2xd, 1H, OH, J=6Hz), 3.4 (t, 1H, im, J=6Hz), 3.3 (m, 2H, H22), 3.1 (m, 1H, NCH), 1.2, 1.25 (2xs, 3H , CH3CS)- 1.18, 1.45 (2xs, (CH3)15,. (CH3)! 8), 0.9 (m, 6H, CH(CH3)2), 0.75, 0.88 (2xd, (CH3)16, (CH3) 17, J = 5.4 Hz) _ Example 21a 14-0-[(3-(R*)-fluorenyl-cyclohexylmethyl-1-yl)-ethenyl] truncated, in the form of the hydrochloride + 14-0-[(3-(S*)· Pulse 'yl-cyclohexan-1-(S*)-methyl-1-yl)-ethyl aryl) truncation, in the form of hydrochloride (d6 -DMSO) : 10.7, 8.6, 7.65, (3xm, 2H, NH), 6.7-7.5 (b, 2H, NH), 6.15, 5.1 (2xm, Η! 9, H2 〇, H21), 5.52 (d, 1H , J=5.2Hz, H! 4), 5.5 (d, 1H, OH, J=6Hz), 3.9, 3.6 (2xm, 1H, CHNH), 3.4 (t, 1H, H:}, J=6Hz), 3.3 (m, 2H, H2 2), 1.4, 1. 45 (2xs, 3H, CH3 CS), 1.18, 1.45 (2xs, (CH3 h 5, (CH3)! 6), 0.75, 0.88 (2xd, (CH3), 6, (CH3)17} J=5.4Hz) Example 21b 14-0-[(3-(R*)-indolyl-cyclohexan-1-(S*)-methyl-1-yl)-ethenyl] truncated as a hydrochloride salt + l4-〇-[(3-(S*)-fluorenyl-cyclohexylmethyl-1-yl)ethenyl] truncated as a hydrochloride salt (d6-DMSO): 10.7, 8.6, 7.65 , (3xm, 2H, NH), 6.7-7.5 (b, 2H, NH), 6.15, 5.1 (2xm, H! 9, H2 〇, H2 !), 5.52 (d, 1H, J=5.2Hz, Hj 4 ), 5.5 (d, 1H, OH, J=6Hz), 3.9, 3.6

84364 -37- rI33191684364 -37- rI331916

RexRex

(2xm, 1H, CHNH), 3.4 (t, 1H, Η2!, J=6Hz), 3.3 (m, 2H, H22), 1.4, 1.45 (2xs, 3H, CH3 CS), 1.18,1.45 (2xs, (CH3)! 5, (CH3), 8 )5 0.75, 0.88 (2xd, (CH3), 6, (CH3)17, J=5.4Hz)_ 實例22a 14-0-[(3_(R*)-(R)-異纈草胺醯基胺基 甲基-1-基)硫基）-乙醯基】截短素與14-0-[(3-(S*)-(R)_異纈草胺醯基胺基-1-(S*)-甲基-1-基) 硫基)-乙醯基】截短素，呈鹽酸鹽形式（非 對映異構混合物） (d6-DMSO) ： 8.3 (m, 1H, NHC=0), 8.1 (b, 3H, NH3 + )，6.15, 5.1 (2xm, 9，H2 〇，H2 i )，5.52 (d, 1H， J=5.2Hz,叶 4)，3.9 (m，1H，a-H-異纈草胺醯基）， 3.3-3.1 (4xm，4H，力！，H2 2，CHNH3 + )，4.5 (b，1H， OH), 1.25 (b, 3H, CH3 CS), 1.18, 1.45 (2xs, (CH3 \ 5, (CH3)! 8), 0.9 (m, 6H, CH(CH3 )2 ), 0.75, 0.88 (2xd, (CH3)16，(CH3)17，J=5.4Hz) 實例22b l4-0-[(3-(R*)-(R)-異纈草胺醯基胺基-l-(S*；j-甲 基-1-基)硫基）乙醯基】截短素與l4_0-[(3-(S*)-(R)-異纈草胺醯基胺基曱基1_基）硫 基)·乙醯基】截短素，呈鹽酸鹽形式（非對 映異構混合物） (d6-DMSO) ： 8.35 (m, 1H, NHC=0), 8.1 (b, 3H, NH3 + )，6.15, 5_ 1 (2xm，氏 9，H2 〇，H2 丨），5·52 (d, 1H， J=5.2Hz，Hi 4), 3.95 (m, 1H，a-H-異纈草胺醯基）， 3.75 (m，1H，CHNH)，3.2-3.5 (3xm，3H，① i，H2 2 )， 4.5 (b, 1H, OH), 1.25 (b, 3H, CH3CS), 1.18, 1.45 (2xs, (CH3), 5, (CH3), 8 )5 0.9 (m, 6H, CH(CH3 )2), 0.75, 0.88 (2xd, (CH3)! 6, (CH3 ^ 7, J=5.4Hz)(2xm, 1H, CHNH), 3.4 (t, 1H, Η2!, J=6Hz), 3.3 (m, 2H, H22), 1.4, 1.45 (2xs, 3H, CH3 CS), 1.18, 1.45 (2xs, ( CH3)! 5, (CH3), 8)5 0.75, 0.88 (2xd, (CH3), 6, (CH3)17, J=5.4Hz)_ Example 22a 14-0-[(3_(R*)-( R)-isosauryl-decylaminomethyl-1-yl)thio)-ethenyl] truncated and 14-0-[(3-(S*)-(R)_isoform Amidino-amino-1-(S*)-methyl-1-yl)thio)-ethenyl] truncated, in the form of the hydrochloride (diastereomeric mixture) (d6-DMSO) : 8.3 (m, 1H, NHC=0), 8.1 (b, 3H, NH3 + ), 6.15, 5.1 (2xm, 9, H2 〇, H2 i ), 5.52 (d, 1H, J=5.2Hz, leaf 4 ), 3.9 (m, 1H, aH-isoxazone), 3.3-3.1 (4xm, 4H, force!, H2 2, CHNH3 + ), 4.5 (b, 1H, OH), 1.25 (b, 3H) , CH3 CS), 1.18, 1.45 (2xs, (CH3 \ 5, (CH3)! 8), 0.9 (m, 6H, CH(CH3 )2 ), 0.75, 0.88 (2xd, (CH3)16, (CH3) 17, J = 5.4 Hz) Example 22b l4-0-[(3-(R*)-(R)-isosaurinylamino-l-(S*;j-methyl-1-yl) Thio)ethylidene] truncated and l4_0-[(3-(S*)-(R)-isochlorinyl indenylamino)-yl) thio)·ethinyl] truncated Hydrochloride Form (diastereomeric mixture) (d6-DMSO): 8.35 (m, 1H, NHC=0), 8.1 (b, 3H, NH3 + ), 6.15, 5_ 1 (2xm, 9, H2 〇, H2丨),5·52 (d, 1H, J=5.2Hz, Hi 4), 3.95 (m, 1H, aH-isosazone oxime), 3.75 (m, 1H, CHNH), 3.2-3.5 (3xm ,3H,1 i,H2 2 ), 4.5 (b, 1H, OH), 1.25 (b, 3H, CH3CS), 1.18, 1.45 (2xs, (CH3), 5, (CH3), 8 )5 0.9 (m , 6H, CH(CH3 )2), 0.75, 0.88 (2xd, (CH3)! 6, (CH3 ^ 7, J=5.4Hz)

84364 -38- 133191684364 -38- 1331916

RexRex

實例23 14-0-[(3-(R/S)-二甲胺基-亞甲亞胺基-環己-1-(R/S)-甲基·1_基)-乙醯基】截短素，呈鹽酸里 形式 (d6-DMSO) ： 9.2, 8.1 (2xb, 2H, NH), 6.15, 5.1 (2xm, Hi 9, H2 〇, H2!), 5.52 (d, 1H, J=5.2Hz, H! 4), 4.5 (d, 1H, OH, J=6Hz), 3.7 (m, 1H, CHNH), 3.4 (t, 1H, Hj!, J=6Hz), 3.3 (m, 2H, H22), 3.1 (b, 6H, N(CH3)2)5 1.4, 1.45 (2xs, 3H，CH3 CS)，1.18, 1.45 (2xs, (CH3 5， (CH3 h 8 )，0.75, 0.88 (2xd，（CH3 久 6，（CH3 h 7，J= ' 5.4Hz)_ _ 於另一方面，本發明係提供14-0-(羥亞胺基-(C3-8)環烷基-硫 基甲基羰基）-截短側耳素與14-0-(亞肼基-(C3_8)環烷基-硫基甲 基羰基）-截短側耳素，譬如下式化合物Example 23 14-0-[(3-(R/S)-Dimethylamino-methyleneimido-cyclohexan-1-(R/S)-methyl·1-yl)-ethenyl] Truncated in the form of hydrochloric acid (d6-DMSO): 9.2, 8.1 (2xb, 2H, NH), 6.15, 5.1 (2xm, Hi 9, H2 〇, H2!), 5.52 (d, 1H, J=5.2 Hz, H! 4), 4.5 (d, 1H, OH, J=6Hz), 3.7 (m, 1H, CHNH), 3.4 (t, 1H, Hj!, J=6Hz), 3.3 (m, 2H, H22 ), 3.1 (b, 6H, N(CH3)2)5 1.4, 1.45 (2xs, 3H, CH3 CS), 1.18, 1.45 (2xs, (CH3 5, (CH3 h 8 ), 0.75, 0.88 (2xd, ( CH3 long 6, (CH3 h 7, J = '5.4 Hz) _ _ In another aspect, the present invention provides 14-0-(hydroxyimino-(C3-8)cycloalkyl-thiomethylcarbonyl ) - pleuromutilin and 14-0-(indolyl-(C3_8)cycloalkyl-thiomethylcarbonyl)-pleuromutilin, a compound of the formula

其中 R1B具有如上文定義之RlA之意義， Kb具有如上文定義之r2a之意義， R1〇B具有如上文定義之心八之意義， 虛線具有如上文定義之意義， 叫具有如上文定義之叫之意義， R3B為氫或(U燒基， 84364 -39- XB 為-O-R4 B 或 _nr5 B % b， ^為氫或(Cl.6)燒基，視情況被基H-nr7bR8B取代，' R5B與係互相獨立為（Ci4)烷基， R*7B與心1係互相獨立為（(：卜4成基，或 R7B與R8B和彼等所連接之氮原子—起形成具有5至8 之脂族雜環基，及 月Wherein R1B has the meaning of R1A as defined above, Kb has the meaning of r2a as defined above, R1〇B has the meaning of a heart eight as defined above, and the dotted line has the meaning as defined above, and has a definition as defined above Meaning, R3B is hydrogen or (U-based, 84364 -39- XB is -O-R4 B or _nr5 B % b, ^ is hydrogen or (Cl.6) alkyl, optionally replaced by H-nr7bR8B, 'R5B is independent of each other as (Ci4) alkyl, R*7B and core 1 are independent of each other ((: 4, or R7B and R8B and their attached nitrogen atoms) form 5 to 8 Aliphatic heterocyclic group, and month

R9 B為氫或（Ci · 4 )燒&gt; 基P 在式IB化合物中’較佳情況是 -R1B為氫， -β·2Β為氫， -虛線不存在（單鍵）， mB 為 2、3 或 4， • R3B為氫或（Ο!·#)烷基，譬如甲基， -Xb係如·上文定義， _ R4B為氫或（C1M)烷基，譬如乙基，被基團取代， _ R5B與R^B均如上文定義， • 與係互相獨立為（Cl_4)烷基，例如乙基，或R7b與Km 和彼等所連接之氮原子一起形成四氫吡咯或六氫吡啶， • ^9Β係如上文定義，及 • Rl 0B為氣； 例如，包括14-0-(羥亞胺基_(C3-8)環烷基_硫基甲基羰基）_截短 側耳素與14_〇-(亞肼基-(C3-8)環烷基-硫基甲基羰基）-截短侧耳 素’其係選自包括下式化合物， 84364 1331916R9 B is hydrogen or (Ci · 4 ) calcined &gt; base P In the compound of formula IB, it is preferred that -R1B is hydrogen, -β·2Β is hydrogen, - a dotted line is absent (single bond), mB is 2 3 or 4, • R3B is hydrogen or (Ο!·#)alkyl, such as methyl, -Xb is as defined above, _ R4B is hydrogen or (C1M)alkyl, such as ethyl, substituted by a group , _ R5B and R^B are as defined above, • the system is independently (Cl_4) alkyl, such as ethyl, or R7b forms a tetrahydropyrrole or a hexahydropyridine together with Km and the nitrogen atom to which they are attached. • ^9Β is as defined above, and • Rl 0B is gas; for example, including 14-0-(hydroxyimino-(C3-8)cycloalkyl-thiomethylcarbonyl)-pleuromutilin and 14 _〇-(indenyl-(C3-8)cycloalkyl-thiomethylcarbonyl)-pleuromutilin' is selected from compounds including the following formula, 84364 1331916

其中REX係如表3中所列示者。所描述及根據例如類似如實 例中所述之方法所獲得之化合物，其1H-NMR數據亦顯示於 表3中： _ 表3Among them, REX is as listed in Table 3. The 1H-NMR data described and according to, for example, a compound obtained by a method similar to that described in the examples are also shown in Table 3: _ Table 3

實例24 14-0-{[(3-羧亞胺基-環戊-(R/S)-基)-硫基]•乙 醯基}-截短素（同側與對側形式） 同側 *-形式：（DMSO-d6) : 10.33 (s，1H，=N0H)， 6.15, 5.07, 5.03 (3xm, 9, H2 〇, H2 !), 5.55 (d, 1H, H14, J=8.3Hz), 4.5 (d, 1H, 11-OH, J=6.1Hz), 3.25-. 3.45 (m, SCH, Hj!, H22), 2.67 (m, 1H, H-2a'), 1.35, 1.05 (2xs, (CH3)! 5, (CH3)! 8), 0.8, 0.62 (2xd, (CH3)16,(CH3)17,J=7Hz). 對側 *-形式：（DMSO-d6): 10.36(s，1H，=NOH), 6.15,5.07,5.02 (3xm, ^ 9, H2〇, H2 ! ), 5.55 (d, 1H, H14, J=8.3Hz), 4.5 (d, 1H, 11-OH, J=6.1Hz), 3.25- 3.45 (m，SCH，&amp; i，H22), 2.74 (m, 1H，H-2a，）1.35， 1.05 (2xs, (CH3 )i 5, (CH3)! 8), 0.8, 0.62 (2xd, (CH3)! 6, (CH3)! 7, J=6.8Hz) 84364 • 41 · 1331916Example 24 14-0-{[(3-carboxyimino-cyclopentyl-(R/S)-yl)-thio]-ethenyl}- truncated (same and contralateral forms) ipsilateral *-Form: (DMSO-d6): 10.33 (s,1H,=N0H), 6.15, 5.07, 5.03 (3xm, 9, H2 〇, H2 !), 5.55 (d, 1H, H14, J=8.3Hz) , 4.5 (d, 1H, 11-OH, J=6.1Hz), 3.25-. 3.45 (m, SCH, Hj!, H22), 2.67 (m, 1H, H-2a'), 1.35, 1.05 (2xs, (CH3)! 5, (CH3)! 8), 0.8, 0.62 (2xd, (CH3)16, (CH3)17, J=7Hz). Contralateral*-form: (DMSO-d6): 10.36(s, 1H,=NOH), 6.15,5.07,5.02 (3xm, ^ 9, H2〇, H2 ! ), 5.55 (d, 1H, H14, J=8.3Hz), 4.5 (d, 1H, 11-OH, J= 6.1 Hz), 3.25- 3.45 (m, SCH, &amp; i, H22), 2.74 (m, 1H, H-2a,) 1.35, 1.05 (2xs, (CH3)i 5, (CH3)! 8), 0.8 , 0.62 (2xd, (CH3)! 6, (CH3)! 7, J=6.8Hz) 84364 • 41 · 1331916

Rex 實例25a -14-0-{【(3-(E/Z)·經亞胺基-1-曱基-環戊-(R*)-基 )-硫基】-乙醯基}-截短素 1HNMR(DMSO-d6): 10.33, 10.28 (2xs，1H,=N0H)， 6.15, 5.07, 5.02 (3xm, Hj 9, H2 〇, H2 i), 5.55, 5.53 (2xd, 1H, H! 4, J=8.3Hz), 4.5, 4.48 (2xd, 1H, 11-OH, J=6.0Hz), 3.20-3.45 (m, SCH，叫丨，H22)，1.35, 1.05 (3xs, CH3 CS, (CH3)! 5, (CH3)! 8), 0.8, 0.62 (2xd, (CH3 )j 6, (CH3)! 7, J=6.9Hz) 實例25b 14-0-{[(3-(E/Z)·羥亞胺基-1-甲基環戊-(S*)-基 )-硫基]-乙醯基}-截短素 (DMSO-d6) ： 10.32,10.27 (2xs, 1H, =NOH), 6.15, 5.07, 5.02 (3xm, Hj 9, H2 〇, H2 !), 5.55 (d, 1H, Hj 4, J=8.3Hz), 4.5 (d, 1H, 11-OH, J=6.1Hz), 3.20-3.45 (m, SCH, H!!, H2 2), 1.35, 1.05 (3xs, CH3 CS, (CH3 ^ 5, (CH3 8), 0.8, 0.62 (2xd, (CH3), 6, (CH3 )j 7, J= 6.8Hz) Rex 實例26 14-0_{[(3-(2-二乙胺基-乙氧基亞胺基）-環戊-(R/s)-基）-硫基]乙醯基}-截短素，呈鹽酸鹽 %/\^n(c2hs)2 形式（同侧/對側混合物） (DMSO-d6) ： 9.9 (bs, 1H,NH+)S 6.15, 5.07, 5.03 (3xm, Η! 9, H2 〇, H2 !), 5.55 (d, 1H, H! 4, J=8.1Hz), 4.3 (% 2H, OCH2 )，3.1-3.4 (m, NCH2，氏！，H2 2 )， 1.35, 1.05 (2xs, (CH3 )i 5, (CH3 )i g), 0.8, 0.62 ( 2xd, (CH3)16，(CH3)17，J=6.8Hz) 84364 -42- 1331916Rex Example 25a -14-0-{[(3-(E/Z)·Iminoamino-1-indenyl-cyclopentyl-(R*)-yl)-thio]-ethenyl}- Short 1H NMR (DMSO-d6): 10.33, 10.28 (2xs, 1H, =N0H), 6.15, 5.07, 5.02 (3xm, Hj 9, H2 〇, H2 i), 5.55, 5.53 (2xd, 1H, H! 4 , J=8.3Hz), 4.5, 4.48 (2xd, 1H, 11-OH, J=6.0Hz), 3.20-3.45 (m, SCH, 丨, H22), 1.35, 1.05 (3xs, CH3 CS, (CH3 5! (CH3)! 8), 0.8, 0.62 (2xd, (CH3)j 6, (CH3)! 7, J=6.9Hz) Example 25b 14-0-{[(3-(E/Z) ·Hydroxyimido-1-methylcyclopenta-(S*)-yl)-thio]-ethenyl}- truncated hormone (DMSO-d6): 10.32, 10.27 (2xs, 1H, =NOH) , 6.15, 5.07, 5.02 (3xm, Hj 9, H2 〇, H2 !), 5.55 (d, 1H, Hj 4, J=8.3Hz), 4.5 (d, 1H, 11-OH, J=6.1Hz), 3.20-3.45 (m, SCH, H!!, H2 2), 1.35, 1.05 (3xs, CH3 CS, (CH3 ^ 5, (CH3 8), 0.8, 0.62 (2xd, (CH3), 6, (CH3 ) j 7, J = 6.8 Hz) Rex Example 26 14-0_{[(3-(2-diethylamino-ethoxyimino)-cyclopentyl-(R/s)-yl)-thio] Acetyl}- truncated, in the form of hydrochloride %/\^n(c2hs)2 (i-side/contralateral mixture) (DMSO-d6): 9.9 (bs, 1H, NH+)S 6.15, 5.07, 5.03 (3xm, Η! 9, H 2 〇, H2 !), 5.55 (d, 1H, H! 4, J=8.1Hz), 4.3 (% 2H, OCH2 ), 3.1-3.4 (m, NCH2, ‧, H2 2 ), 1.35, 1.05 ( 2xs, (CH3 )i 5, (CH3 )ig), 0.8, 0.62 ( 2xd, (CH3)16, (CH3)17, J=6.8Hz) 84364 -42- 1331916

Rex H0&lt; 實例27a14-0-[((E*-肟基-環己-3-(R*)-基)-硫基)-乙醯 基】截短素 T J (d6-DMSO) : 10.31 (s，1Η, HON=C)，6.15, 5.1 (2xm， Η! 9, H2〇, H2!), 5.52 (d, 1H, J=5.2Hz, 4), 4.55 (d, 1H, OH, J=5Hz) 3.4 (t, 1H, 2, J=5Hz), 3.3 (m, 2H, H22), 2.95 (m, 1H, SCH), 2.78, 1.95 (2xm, 2H, CH2C=N), 2.57, 2.09 (2xm, 2H, CH2=C=N), 1.18, 1.45 (2xs, (CH3 )t 5, (CH3)! 8), 0.75, 0.88 (2xd, (CH3)! 6, (CH3), 7, J=5.4Hz). [ o:]D=15.87° (c=l,' MeOH) 實例27b l4-0-[((E*-肪基-環已-3-(S*)-基)-硫基）-乙醯基 ]截短素 (d6-DMSO) ： 10.31 (s, 1H, HON=C), 6.15, 5.1 (2xm, H! 9, H2 〇, H2!), 5.52 (d, 1H, J=5.2Hz, H! 4), 4.50 (d, 1H，OH，J=5Hz) 3.4 (t，1H，％ i，J=5Hz), 3.3 (m, 2H, - Η22), 2.95 (m, 1H, SCH), 2.78, 1.95 (2xm, 2H, CH2C=N), 2.57, 2.09 (2xm, 2H, CH2=C=N), 1.18, 1.45 (2xs, (CH3 )j 5, (CH3 )j 8), 0.75, 0.88 (2xd, (CH3), 6, (CH3)! 7, J=5.4Hz). [ a]D =38.5° (c=l, MeOH) 實例27c14-0-[((Z*-肪基-環己-3-(R*)-基）-硫基）-乙贐 基】截短素 (d6 -DMSO) ： 10.31 (s, 1H, HON=C), 6.15, 5.1 (2xm, Hi 9, H2 〇, H2 !), 5.52 (d, 1H, J=5.2Hz, H! 4), 4.50 (d, 1H, OH, J=5Hz), 3.45 (t, 1H, x, J=5Hz), 3.3 (m, 2H, H2 2 ), 2.90 (m, 1H, SCH), 3.05, 2.05 (2xm, 2H, CH2C=N), 2.2 (m, 2H, CH2=C=N), 1.18, 1.45 (2xs, _(CH3)t 5,(^3)! 8), 0.75,0.88 (2xd, (CH3)i6,Rex H0&lt; Example 27a14-0-[((E*-indolyl-cyclohex-3-(R*)-yl)-thio)-ethinyl] truncated TJ (d6-DMSO): 10.31 ( s,1Η, HON=C), 6.15, 5.1 (2xm, Η! 9, H2〇, H2!), 5.52 (d, 1H, J=5.2Hz, 4), 4.55 (d, 1H, OH, J= 5Hz) 3.4 (t, 1H, 2, J=5Hz), 3.3 (m, 2H, H22), 2.95 (m, 1H, SCH), 2.78, 1.95 (2xm, 2H, CH2C=N), 2.57, 2.09 ( 2xm, 2H, CH2=C=N), 1.18, 1.45 (2xs, (CH3)t 5, (CH3)! 8), 0.75, 0.88 (2xd, (CH3)! 6, (CH3), 7, J= 5.4 Hz). [o:]D=15.87° (c=l, 'MeOH) Example 27b l4-0-[((E*-Amino-cyclohexyl-3-(S*)-yl)-thio) )-Ethyl) truncation (d6-DMSO): 10.31 (s, 1H, HON=C), 6.15, 5.1 (2xm, H! 9, H2 〇, H2!), 5.52 (d, 1H, J 5.2 Hz (d, 1H, OH, J = 5 Hz) , SCH), 2.78, 1.95 (2xm, 2H, CH2C=N), 2.57, 2.09 (2xm, 2H, CH2=C=N), 1.18, 1.45 (2xs, (CH3)j 5, (CH3)j 8) , 0.75, 0.88 (2xd, (CH3), 6, (CH3)! 7, J=5.4Hz). [ a]D =38.5° (c=l, MeOH) Example 27c14-0-[((Z*- Fatty-cyclohexan-3-(R*)-yl)-thio)-ethenyl] truncation (d6-DMSO): 10. 31 (s, 1H, HON=C), 6.15, 5.1 (2xm, Hi 9, H2 〇, H2 !), 5.52 (d, 1H, J=5.2Hz, H! 4), 4.50 (d, 1H, OH , J=5Hz), 3.45 (t, 1H, x, J=5Hz), 3.3 (m, 2H, H2 2 ), 2.90 (m, 1H, SCH), 3.05, 2.05 (2xm, 2H, CH2C=N) , 2.2 (m, 2H, CH2=C=N), 1.18, 1.45 (2xs, _(CH3)t 5,(^3)! 8), 0.75,0.88 (2xd, (CH3)i6,

84364 -43 - 133191684364 -43 - 1331916

(CH3 )ι 7, J=5.4Hz). [ a]O =13.62° (c=l, MeOH) 實例27d 14-0-[((Z*-肘基-環己-3-(S*)-基)-硫基）乙醯基J 截短素(d6-DMSO) ： 10.31 (s, 1H, HON=C), 6.15, 5.1 (2xm, Hi 9, H2 〇, H2 !), 5.52 (d, 1H, J=5.2Hz, R, 4), 4.50 (d, 1H，OH，J=5Hz)，3.45 (t，1H，&amp; 丨，J=5Hz)，3.3 (m， 2H, H2 2), 2.90 (m, 1H, SCH), 3.05, 2.05 (2xm, 2H, CH2C=N), 2.2 (m, 2H, CH2=C=N), 1.18,1.45 (2xs, (CH3 5, (CH3 )! 8), 0.75, 0.88 (2xd, (CH3){ 6, (CH3 7, J=5.4Hz). [ a]D =42.83° (c=l, MeOH) 實例28a 14-0-[((E-肟基-環己-3-(R/S)-甲基-1-基)-硫基） 乙醯基】截短素 (d6-DMSO) ： 10.31 (s, 1H, HON=C), 6.15, 5.1 (2xm, Hi 9, H2 〇, H2 j ), 5.52 (d, 1H, J=5.2Hz, H! 4), 4.50 (d, 1H, OH, J=5Hz), 3.45 (t, 1H, H! t, J=5Hz), 3.25 (m, 2H, H2 2), 1.25 (s, 3H, CH3, CH3 CS) 1.18, 1.45 (2xs, (CH3)! 5, (CH3 )i 8 )5 0.75, 0.88 (2xd, (CH3 )γ 6,' (CH3)17, J=5.4Hz) 實例28b 14-0-[((1肋基-環己-3-(R/S)-甲基-1-基）硫基） 乙贐基】截短素 (d6-DMSO) ： 10.31 (s, 1H, HON=C), 6.15, 5.1 (2xm, H! 9, H2 〇, H2!), 5.52 (d, 1H, J=5.2Hz, 4), 4.50 (d, 1H, OH, J=5Hz), 3.45 (t, 1H, H! t, J=5Hz), 3.25 (m, 2H, H22), 2.7 (d, 1H, CHC=N, J=12Hz), 1.25 (s, 3H, CH3, CH3 CS) 1.18, 1.45 (2xs, (CH3 )l5i (CH3 )j 8), 0.75, 0.88 (2xd, (CH3 6, (CH3 )x 7, J=5.4Hz)(CH3 )ι 7, J=5.4Hz). [ a]O =13.62° (c=l, MeOH) Example 27d 14-0-[((Z*-erbityl-cyclohex-3-(S*)) -yl)-thio)ethylidene J truncation (d6-DMSO): 10.31 (s, 1H, HON=C), 6.15, 5.1 (2xm, Hi 9, H2 〇, H2 !), 5.52 (d , 1H, J=5.2Hz, R, 4), 4.50 (d, 1H, OH, J=5Hz), 3.45 (t,1H,&amp; 丨, J=5Hz), 3.3 (m, 2H, H2 2) , 2.90 (m, 1H, SCH), 3.05, 2.05 (2xm, 2H, CH2C=N), 2.2 (m, 2H, CH2=C=N), 1.18, 1.45 (2xs, (CH3 5, (CH3 )! 8), 0.75, 0.88 (2xd, (CH3){ 6, (CH3 7, J=5.4Hz). [a]D = 42.83° (c=l, MeOH) Example 28a 14-0-[((E- Mercapto-cyclohex-3-(R/S)-methyl-1-yl)-thio)ethylidene] truncation (d6-DMSO): 10.31 (s, 1H, HON=C), 6.15 , 5.1 (2xm, Hi 9, H2 〇, H2 j ), 5.52 (d, 1H, J=5.2Hz, H! 4), 4.50 (d, 1H, OH, J=5Hz), 3.45 (t, 1H, H! t, J=5Hz), 3.25 (m, 2H, H2 2), 1.25 (s, 3H, CH3, CH3 CS) 1.18, 1.45 (2xs, (CH3)! 5, (CH3 )i 8 )5 0.75 , 0.88 (2xd, (CH3)γ 6, '(CH3)17, J=5.4Hz) Example 28b 14-0-[((1 rib-cyclohex-3-(R/S)-methyl-1) -yl)thio)ethylidene] truncation (d6-DMSO): 10.31 (s, 1H, HON=C), 6.15, 5. 1 (2xm, H! 9, H2 〇, H2!), 5.52 (d, 1H, J=5.2Hz, 4), 4.50 (d, 1H, OH, J=5Hz), 3.45 (t, 1H, H! t, J=5Hz), 3.25 (m, 2H, H22), 2.7 (d, 1H, CHC=N, J=12Hz), 1.25 (s, 3H, CH3, CH3 CS) 1.18, 1.45 (2xs, (CH3 )l5i (CH3 )j 8), 0.75, 0.88 (2xd, (CH3 6, (CH3)x 7, J=5.4Hz)

84364 -44 - 133191684364 -44 - 1331916

Rex ch3 II 實例29 14-0_[((Z/E-肟基-環己-3-(R/S)-曱基-5-(R/S)-甲 基-1-基)-硫基）乙酿基]截短素 (d6-DMSO):非對映異構物：10.2, 10.28 (3xs，1H， 1 OH HON=C)，6.15, 5_1 (2xm，Η! 9, H20, H2 !)，5.52 (d， 1H, J=5.2Hz, Hi 4), 4.50 (d, 1H, OH, J=5Hz), 3.45 (t, 1H, Hi!, J=5Hz), 3.25 (m, 2H, H22), 3.25, 1.7 (2xm, 2H, CH2 C=N), 1.3, 1.34 (2xs, 3H, CH3, CH3 CS), 1.18, 1.45 (2xs, (CH3 )l5, (CH3 )t 8 ), 0.75, 0.88 (2xd, (CH3)16, (CH3)17, J=5.4Hz)· * MS-ESI ： 534 (M+l) Rex N&gt;〇/-v^N(C2H5)2 實例30 14-0-{【(3-(2-二乙胺基-乙氧基亞胺基)-環己· (R/S)-基)-硫基]-乙醯基}-截短素鹽酸鹽(E/Z 混合物） (DMSO-d6) ： 9.7 (bs, 1H, NH+), 6.15, 5.07, 5.03 (3xm，9，H2 〇，H2! )，5.55 (d，1H，此 4，J=8.0Hz)， 4.5, 4.25 (2xm，2H，OCH2 ), 3.0-3.45 (m，NCH2，Hi i， H2 2 )，1.35,1.05 (2xs，（CH3 h 5，（CH3 h 8 )，0.8,0.62 (2xd, (CH3 )t 6, (CH3)! 7, J=6.8Hz) Rex ςτ 實例31 14-0-[(((E/Z)-二甲基胺基亞胺基·環己-3-(R/S)-l-基）-硫基）乙醯基】截短素 h3c、n^n (d6-DMSO):非對映異構物：6.15, 5.1 (2xm，氏 9, H2 〇，H2 i )，5.52 (d，1H，J=5.2Hz，Η! 4 )，4·50 (d，1H， OH, J=5Hz), 3.45 (t, 1H, Hj!, J=5Hz), 3.3 (m, 2H, H22), 3.2, 2.8 (2xm, 1H, CHS), 2.95, 1.85 (2xm, 2H, CH2 C=N), 1.18, 1.45 (2xs, (CH3), 5, (CH3 8 ), 0.75, 0.88 (2xd, (CH3 )t 6, (CH3 )x 7, J=5.4Hz) 84364 • 45- 1331916Rex ch3 II Example 29 14-0_[((Z/E-fluorenyl-cyclohex-3-(R/S)-fluorenyl-5-(R/S)-methyl-1-yl)-thio) Ethyl] truncation (d6-DMSO): diastereomers: 10.2, 10.28 (3xs, 1H, 1 OH HON=C), 6.15, 5_1 (2xm, Η! 9, H20, H2 ! ), 5.52 (d, 1H, J=5.2Hz, Hi 4), 4.50 (d, 1H, OH, J=5Hz), 3.45 (t, 1H, Hi!, J=5Hz), 3.25 (m, 2H, H22), 3.25, 1.7 (2xm, 2H, CH2 C=N), 1.3, 1.34 (2xs, 3H, CH3, CH3 CS), 1.18, 1.45 (2xs, (CH3 )l5, (CH3 )t 8 ), 0.75 , 0.88 (2xd, (CH3)16, (CH3)17, J=5.4Hz)· * MS-ESI : 534 (M+l) Rex N&gt;〇/-v^N(C2H5)2 Example 30 14-0 -{[(3-(2-diethylamino-ethoxyimino)-cyclohexyl (R/S)-yl)-thio]-ethenyl}- truncated hydrochloride ( E/Z mixture) (DMSO-d6): 9.7 (bs, 1H, NH+), 6.15, 5.07, 5.03 (3xm, 9, H2 〇, H2!), 5.55 (d, 1H, 4, J=8.0Hz ), 4.5, 4.25 (2xm, 2H, OCH2), 3.0-3.45 (m, NCH2, Hi i, H2 2 ), 1.35, 1.05 (2xs, (CH3 h 5, (CH3 h 8 ), 0.8, 0.62 (2xd , (CH3 )t 6, (CH3)! 7, J=6.8Hz) Rex ςτ Example 31 14-0-[(((E/Z)-Dimethylaminoimino]cyclohex-3-( R/S)-l- ))-thio)ethinyl] truncated hormone h3c, n^n (d6-DMSO): diastereomer: 6.15, 5.1 (2xm, 9, H2 〇, H2 i ), 5.52 (d , 1H, J=5.2Hz, Η! 4), 4·50 (d, 1H, OH, J=5Hz), 3.45 (t, 1H, Hj!, J=5Hz), 3.3 (m, 2H, H22) , 3.2, 2.8 (2xm, 1H, CHS), 2.95, 1.85 (2xm, 2H, CH2 C=N), 1.18, 1.45 (2xs, (CH3), 5, (CH3 8 ), 0.75, 0.88 (2xd, ( CH3 )t 6, (CH3 )x 7, J=5.4Hz) 84364 • 45- 1331916

Rex 實例32a 14-0-[((E*-肟基-環庚-3-(R/S)-基)-硫基)-乙醢 基】截短素 NMR(d6-DMSO) ： 10.35 (s, 1H, HON=C), 6.15, 5.1 VH (2xm, Hi 9, H2 〇, H2 !), 5.52 (d, 1H, J=5.2Hz, H! 4), &quot; 4.5 (d, 1H, OH, J=6.1Hz), 3.4 (t, 1H, H!!, J=6.1Hz)), 3.3 (m, 2H, H2 2), 1.18, 1.45 (2xs, (CH3 )x 5, (CH3 \ 8) ,0.75, 0.88 (2xd, (CH3): 6, (CH3 7, J=5.4Hz). 實例32b 14-0-[((Z*-肟基-環庚-3-(R/S)-基）-硫基）乙酿 基】截短素 一 (d6-DMSO) ： 10.35 (s, 1H, HON=C), 6.15, 5.1 (2xm, Hi 9, H2 〇, H2 !), 5.52 (d, 1H, J=5.2Hz, H! 4), 4.5 (d5 1H，OH，J二5Hz) 3.4 (t，1H，H! i，J=5Hz)，3.3 (m，2H, H2 2 )，3_05 (m，1H，SCH)，1.18, 1.45 (2xs，（CH3 h 5， (CH3 h 8 )，0.75, 0.88 (2xd，（CHJ 6，（CH3 h 7，J=Rex Example 32a 14-0-[((E*-fluorenyl-cyclohept-3-(R/S)-yl)-thio)-ethenyl] truncated NMR (d6-DMSO): 10.35 ( s, 1H, HON=C), 6.15, 5.1 VH (2xm, Hi 9, H2 〇, H2 !), 5.52 (d, 1H, J=5.2Hz, H! 4), &quot; 4.5 (d, 1H, OH, J=6.1Hz), 3.4 (t, 1H, H!!, J=6.1Hz)), 3.3 (m, 2H, H2 2), 1.18, 1.45 (2xs, (CH3)x 5, (CH3 \ 8), 0.75, 0.88 (2xd, (CH3): 6, (CH3 7, J=5.4Hz). Example 32b 14-0-[((Z*-Mercapto-cycloheptan-3-(R/S)) -yl)-thiol)diyl] truncation-one (d6-DMSO): 10.35 (s, 1H, HON=C), 6.15, 5.1 (2xm, Hi 9, H2 〇, H2 !), 5.52 ( d, 1H, J=5.2Hz, H! 4), 4.5 (d5 1H, OH, J 2 5Hz) 3.4 (t, 1H, H! i, J=5Hz), 3.3 (m, 2H, H2 2 ), 3_05 (m, 1H, SCH), 1.18, 1.45 (2xs, (CH3 h 5, (CH3 h 8 ), 0.75, 0.88 (2xd, (CHJ 6, (CH3 h 7, J=

RexRex

O 5.4Hz)_ 實例33 14-0-{[(3-(2-二乙胺基-乙氧基亞胺基)-環庚_ (R/S)-基)-硫基】-乙酼基}-截短素鹽酸鹽（E/Z 混合物） (DMSO-d6) ： 9.85 (bs, 1H, NH+), 6.15, 5.06, 5.03 (3xm, Hi 9, H2 〇, H2!), 5.55 (d, 1H, Hj 4, J=8.5Hz), 4.52, 4.53 (2xd, 1H, 11-OH, J=6.2Hz), 4.28 (m, 2H, OCH2 )，3.0-3.45 (m, NCH2，&amp; i，H2 2 )，1.35, 1.05 (2xs5 (CH3 5, (CH38 )5 0.8, 0.62 (2xd, (CH3 )x 6, (CH3)17j J=6.8Hz)O 5.4 Hz) _ Example 33 14-0-{[(3-(2-diethylamino-ethoxyimino)-cycloheptyl-(R/S)-yl)-thio]-acetamidine }-- truncated HCl (E/Z mixture) (DMSO-d6): 9.85 (bs, 1H, NH+), 6.15, 5.06, 5.03 (3xm, Hi 9, H2 〇, H2!), 5.55 ( d, 1H, Hj 4, J=8.5Hz), 4.52, 4.53 (2xd, 1H, 11-OH, J=6.2Hz), 4.28 (m, 2H, OCH2), 3.0-3.45 (m, NCH2, &amp; i, H2 2 ), 1.35, 1.05 (2xs5 (CH3 5, (CH38 )5 0.8, 0.62 (2xd, (CH3 )x 6, (CH3)17j J=6.8Hz)

84364 46- 133191684364 46- 1331916

實例34 14-0-{[(3-(2-四氫吡咯-1-基-乙氧基亞胺基）-環庚-1-(R/S)-基）-硫基】-乙醯基}-截短素鹽酸 鹽（E/Z混合物）- (DMSO-d6) ： 10.2 (bs, 1H, ΝΗ+), 6.15, 5.08, 5.05 (3xm, Η! 9, Η2 〇, Η2,), 5.58 (d, 1Η, Η! 4, J=8.3Hz), 4.53,4.57 (2xd, 1Η, 11-ΟΗ, J=6.1Hz), 4.26 (m, 2H, 00^),3.0-3.45(111^^2,^^¾ 2 ), 1.38, 1.08 (2xs, (CH3 5, (CH3)! 3 ), 0.83, 0.64 (2xd, (CH36, (CH3)17&gt; J=6.8Hz). 'Example 34 14-0-{[(3-(2-Tetrahydropyrrol-1-yl-ethoxyimino)-cycloheptan-1-(R/S)-yl)-thio]-acetamidine }}- truncated HCl (E/Z mixture) - (DMSO-d6) : 10.2 (bs, 1H, ΝΗ+), 6.15, 5.08, 5.05 (3xm, Η! 9, Η2 〇, Η2,) , 5.58 (d, 1Η, Η! 4, J=8.3Hz), 4.53, 4.57 (2xd, 1Η, 11-ΟΗ, J=6.1Hz), 4.26 (m, 2H, 00^), 3.0-3.45 (111 ^^2,^^3⁄4 2 ), 1.38, 1.08 (2xs, (CH3 5, (CH3)! 3 ), 0.83, 0.64 (2xd, (CH36, (CH3)17> J=6.8Hz). '

實例35 14-0-{[(3-(2-六氫吡啶-1-基-乙氧基亞胺基）-環庚-(R/S)-基)-硫基】-乙醯基}-截短素，呈鹽 酸鹽形式（E/Z混合物） 1HNMR(DMSO-d6)： 10.0 (bs, 1H, NH+), 6.15, 5.06, 5.03 (3xm, Hj 9, H2〇, H21), 5.55 (d, 1H, H! 4, J=8.4 Hz), 4.5, 4.55 (2xd, 1H, 11-OH, J=6.2Hz), 4.32 (m, 2H, OCH2 )，2.8-3.5 (m, NCH2，H!!，H2 2 )，1.35, 1-05 (2xs, (CH3 )! 5, (CH3 )! 8 ), 0.8, 0.62 (2xd, (CH3 ^ 6, (CH3)17, J=6.8Hz) _ 於另一方面，本發明係提供下式化合物Example 35 14-0-{[(3-(2-Hexahydropyridin-1-yl-ethoxyimino)-cycloheptyl-(R/S)-yl)-thio]-ethenyl} - truncated, in the form of the hydrochloride (E/Z mixture) 1H NMR (DMSO-d6): 10.0 (bs, 1H, NH+), 6.15, 5.06, 5.03 (3xm, Hj 9, H2, H21), 5.55 (d, 1H, H! 4, J=8.4 Hz), 4.5, 4.55 (2xd, 1H, 11-OH, J=6.2Hz), 4.32 (m, 2H, OCH2), 2.8-3.5 (m, NCH2, H!!, H2 2 ), 1.35, 1-05 (2xs, (CH3 )! 5, (CH3 )! 8 ), 0.8, 0.62 (2xd, (CH3 ^ 6, (CH3)17, J=6.8Hz) _ In another aspect, the invention provides a compound of the formula

其中 R1C具有如上文定義之R1A之意義， S4364 •47- 1331916 R2C具有如上文定義之r2a之意義， 虛線具有如上文定義之意義， R4C具有如上文定義之&amp;A之意義，及 he為胺基' (C1M)烷胺基、二（(^·4)烷胺基、胺基酸之殘基 、喪基或（C1-4)燒氧基。 在式1C化合物中’較佳情況是 ~ Rl c為氫，Wherein R1C has the meaning of R1A as defined above, S4364 • 47-1331916 R2C has the meaning of r2a as defined above, the dotted line has the meaning as defined above, R4C has the meaning of &amp;A as defined above, and he is an amine a base '(C1M)alkylamino group, a di((^.4)alkylamino group, a residue of an amino acid, a sulfhydryl group or a (C1-4) alkoxy group. In the compound of the formula 1C, 'better case is ~ Rl c is hydrogen,

虛線不存在（單鍵） R3 C為胺基、二 早鍵），及 一（Cl-4)燒胺基或胺基酸之殘基； 例如’包括截短側耳素，其係選自包括下式化合物The dotted line is absent (single bond) R3 C is an amine group, a two-early bond), and a residue of a (Cl-4) aromatine or amino acid; for example, 'including pleuromutilin, which is selected from the group consisting of Compound

表4中： 示者。所描述及根據例如類似如實 t化合物，其1H-NMR數據亦顯示於 84364 -48- 1331916 表4 R©cIn Table 4: The presenter. The 1H-NMR data are also described and based on, for example, a similar t-compound, and the 1H-NMR data are also shown in 84364 -48-1331916.

實例36a 14-0-{[(3S,3aS,6S,6aR)-6-胺基-六氫-呋喃并[3,2-b]呋喃-3-基硫基】-乙醯基}-截短素，呈II酸 鹽形式- (DMSO-d6) ： 8.3 (bs, 3H, NH3 + ), 6.15, 5.05, 5.02 (3xm, Η! 9, H2 〇, H2 !), 5.55 (d, 1H, 8.2Hz, H! 4), 4.65, 4.55 (2xm, Ht! -OH, H-3a', H6a'), 3.6-4.1 (m, 5H, H-2', H-5', H-6'), 3.3-3.5 (m, 4H, Η! l, H-3', H22), 1.35, 1.05 (2xs，(CH3)15，(CH3)18)，0.8,0.62(2xd，(CH3)16，-(CH3)17, J=6.5Hz) 實例36b14-0-{[(3R，3aS，6S,6aR)-6-胺基六氫-呋喃并[3,2-b]呋喃-3-基硫基]-乙醯基}-截短素-鹽酸鹽 (DMSO-d6) ： 8.3 (bs, 3Η,ΝΗ3 + ), 6.15, 5.07, 5.03 (3xm, H19,H20,H21), 5.55 (d, 1H, ^4, J=8.2Hz), 4.60, 4.7 (2xm, H-3a', H6a'), 3.6-4.1 (m, 5H, H-2', H-5', H-6')，3·3-3.5 (m，4H，①！，H-3，，H22)，1.35, 1.05, (2xs， (CH3): 5, (CH3)! 8), 0.8, 0.62 (2xd, (CH3 )i 6, (CH3)17, J=6.9Hz) 實例36c 14-0-([(3S，3aS,6R，6aR)-6-胺基-六氫-呋喃并[3,2-叫呋喃-3-基硫基卜乙醯基}-截短素-里酸鹽 (DMSO-d6) ： 8.25 (bs, 3H, NH3 + ), 6.15, 5.06, 5.03 (3xm, Hj 9, H2 〇, H2 1), 5.55 (d, 1H, Hj 4, J=8.4Hz), 4.60 (m, 2H, H-3a', H6a'), 3.55-4.2 (m, 5H, H-2', H-5', H-6，)，3.35-3.5 (m，4H，Η!!，H-3'，H22)，1.35,1.05 (2xs, (CH3)! 5, (CH3), 8,0.8, 0.62 (2xd, (CH3), 6, (CH3 7, J=6.9Hz)Example 36a 14-0-{[(3S,3aS,6S,6aR)-6-Amino-hexahydro-furo[3,2-b]furan-3-ylthio]-ethenyl}- Short, in the form of the acid salt - (DMSO-d6): 8.3 (bs, 3H, NH3 + ), 6.15, 5.05, 5.02 (3xm, Η! 9, H2 〇, H2 !), 5.55 (d, 1H, 8.2Hz, H! 4), 4.65, 4.55 (2xm, Ht! -OH, H-3a', H6a'), 3.6-4.1 (m, 5H, H-2', H-5', H-6' ), 3.3-3.5 (m, 4H, Η! l, H-3', H22), 1.35, 1.05 (2xs, (CH3)15, (CH3)18), 0.8, 0.62 (2xd, (CH3)16, -(CH3)17, J=6.5Hz) Example 36b14-0-{[(3R,3aS,6S,6aR)-6-Aminohexahydro-furo[3,2-b]furan-3-ylsulfur ]-- acetyl group}- truncation-hydrochloride (DMSO-d6): 8.3 (bs, 3Η, ΝΗ3 + ), 6.15, 5.07, 5.03 (3xm, H19, H20, H21), 5.55 (d, 1H, ^4, J=8.2Hz), 4.60, 4.7 (2xm, H-3a', H6a'), 3.6-4.1 (m, 5H, H-2', H-5', H-6'), 3·3-3.5 (m, 4H, 1!, H-3,, H22), 1.35, 1.05, (2xs, (CH3): 5, (CH3)! 8), 0.8, 0.62 (2xd, (CH3) i 6, (CH3)17, J=6.9 Hz) Example 36c 14-0-([(3S,3aS,6R,6aR)-6-Amino-hexahydro-furo[3,2-furan-3 -ylthioethylidene}- truncated-lithoate (DMSO-d6): 8.25 (bs, 3H, NH3 + ), 6.15, 5.06, 5.03 (3xm, Hj 9, H2 〇, H2 1), 5.55 (d, 1H, Hj 4, J=8.4Hz), 4.60 (m, 2H, H-3a', H6a') , 3.55-4.2 (m, 5H, H-2', H-5', H-6,), 3.35-3.5 (m, 4H, Η!!, H-3', H22), 1.35, 1.05 (2xs , (CH3)! 5, (CH3), 8,0.8, 0.62 (2xd, (CH3), 6, (CH3 7, J=6.9Hz)

84364 -49- 1331916 實例3784364 -49- 1331916 Example 37

RexRex

14-0-([(3S，3aS,6S，6aR)-6-二甲胺基-六氫呋喃 并[3,2-b]呋喃-3-基硫基】-乙醯基}-截短素，呈 鹽酸鹽形式 (DMSO-d6) ： 11.25 (bs, 1H,NH+), 6.15, 5.06, 5.03 (3xm, Hj 9, H2 〇, H2 !), 5.55 (d, 1H, H! 4 ,J=8.2Hz), 4.60 (m, 1HS H3a'), 3.3-4.1 (MH-21, H-5', H-6', H-6a', Η!!, H-3', H2 2), 2.8, 2.7 (2xd, 6H, NH+ (CH3 )2, J= 4.5Hz), 1.35, 1.05 (2xs, (CH3 \ 5, (CH3 8 ), 0.8, 0.62 (2xd, (CH3 )i 6, (CH3)! 7, J=6.9Hz) · 實例38a14-0-([(3S,3aS,6S,6aR)-6-dimethylamino-hexahydrofuro[3,2-b]furan-3-ylthio]-ethenyl}-truncated In the form of the hydrochloride salt (DMSO-d6): 11.25 (bs, 1H, NH+), 6.15, 5.06, 5.03 (3xm, Hj 9, H2 〇, H2 !), 5.55 (d, 1H, H! 4 , J=8.2Hz), 4.60 (m, 1HS H3a'), 3.3-4.1 (MH-21, H-5', H-6', H-6a', Η!!, H-3', H2 2) , 2.8, 2.7 (2xd, 6H, NH+ (CH3)2, J= 4.5Hz), 1.35, 1.05 (2xs, (CH3 \ 5, (CH3 8 ), 0.8, 0.62 (2xd, (CH3 )i 6, ( CH3)! 7, J=6.9Hz) · Example 38a

Rex-Rex-

l4-0-{[(3S，3aS,6S,6aR)-6-((R)_胺基-3-甲基-丁醯 基胺基)-六氫-呋喃并[3,24&gt;】呋喃_3-基硫基]-乙醯基}-截短素，呈鹽酸鹽形式 (DMSO-d6) ： 8.65 (d, 1H, NH, J=8.2Hz), 7.8 (bs, 3H, NH3 + )，6.15, 5.07, 5.02 (3xm，氏 9，H2 〇，H2 i )，5.55 (d，1H，5,2Hz，4 )，4.55,4.45 (2xm，3H，i -OH, H-3a，，H6a')，3.6-4.2 (m，5H，H-2’，H-5'，H-6')，3·4-3.5· (m，4H，i，H-3，，H2 2 )，1.35, 1.05 (2xs，（CH3 )i 5， (CH3 \ 8), 0.88, 0.92 (2xd, (CH3 )2 CH, J=6.8Hz)； 0.8, 0.62 (2xd, (CH3 )j 6, (CH3 7, J=6.8Hz) 實例38b 14-0-{[(311，338,68,6311)-6-((11)-胺基-3-曱基-丁醯 基胺基)-六氫-咳喃并[3,2-b]呋喃-3-基硫基卜 乙醯基}-截短素，呈鹽酸鹽形式 (DMSO-d6) ： 8.8 (d, 1H, NH, J=7.1Hz), 8.15 (bs, 3H, NH3 + )，6.15, 5.07, 5.03 (3xm，Η! 9，H2 〇，H2 i )，5.55 (d, 1H, 7.9Hz, Hj 4), 4.6, 4.4 (2xm, 2H,, H-3a', H-6a'), 3.6-4.2 (m，5H，H-2'，H-5，，H-6’)，3.2-3.5 (m，4H，Η!!， H_3，，H2 2 )，1.35, 1.05 (2xs，（CH3)! 5，（CH3 h 8 )，0.89, 0.91 (d, (CH3 )2 CH, J=6.8Hz), 0.8, 0.62 (2xd, (CH3 )Y 6,L4-0-{[(3S,3aS,6S,6aR)-6-((R)-Amino-3-methyl-butanylamino)-hexahydro-furo[3,24&gt;]furan_3 -ylthio]-ethenyl}- truncated, in the form of the hydrochloride (DMSO-d6): 8.65 (d, 1H, NH, J = 8.2 Hz), 7.8 (bs, 3H, NH3 + ), 6.15, 5.07, 5.02 (3xm, 9, H2 〇, H2 i ), 5.55 (d, 1H, 5, 2Hz, 4 ), 4.55, 4.45 (2xm, 3H, i - OH, H-3a,, H6a' ), 3.6-4.2 (m, 5H, H-2', H-5', H-6'), 3·4-3.5· (m, 4H, i, H-3,, H2 2 ), 1.35, 1.05 (2xs,(CH3 )i 5, (CH3 \ 8), 0.88, 0.92 (2xd, (CH3 )2 CH, J=6.8Hz); 0.8, 0.62 (2xd, (CH3 )j 6, (CH3 7, J = 6.8 Hz) Example 38b 14-0-{[(311,338,68,6311)-6-((11)-Amino-3-indolyl-butanylamino)-hexahydro-c-c-[ 3,2-b]furan-3-ylthiopyridinyl}- truncated as hydrochloride (DMSO-d6): 8.8 (d, 1H, NH, J = 7.1 Hz), 8.15 ( Bs, 3H, NH3 + ), 6.15, 5.07, 5.03 (3xm, Η! 9, H2 〇, H2 i ), 5.55 (d, 1H, 7.9Hz, Hj 4), 4.6, 4.4 (2xm, 2H,, H -3a', H-6a'), 3.6-4.2 (m, 5H, H-2', H-5,, H-6'), 3.2-3.5 (m, 4H, Η!!, H_3,, H2 2), 1.35, 1.05 (2xs,(CH3)! 5,(CH3 h 8 ),0.89, 0.91 (d, (CH3 )2 CH, J=6.8Hz), 0.8, 0.62 (2xd, (CH3 )Y 6,

84364 -50- 133191684364 -50- 1331916

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(CH3)18jJ=6.8Hz) 實例38c 14-0-{[(3S,3aS,6R，6aR)-6-((R)-胺基-3-曱基-丁醯 基胺基)-六氫-吱喃并[3,2-b】呋喃-3-基硫基]-乙醯基}-截短素，呈鹽酸鹽形式 (DMSO-d6) ： 8.4 (d, 1H, NH, J=7.8Hz), 8.1 (bs, 3H, NH3 + )，6.15, 5.06, 5.02 (3xm,呒 9，H20，H2 , )，5.55 (d，1H，8.2Hz，4 )，4.6,4.5 (2xm，2H，，H3a'，H6a，)， 3.6-4.4 (m, 5H, H-2', H-5', H-6'), 3.3-3.5 (m, 4H, ^ l, H-3', H2 2), 1.35, 1.05 (2xs, (CH3 \ 5, (CH3), 8 ), 0.94. 0.90 (d, (CH3 )2 CH, J=6.8Hz), 0.8, 0.62 (2xd, (CH3 &gt;! 6, (CH3)17,J=6.8Hz)_ 實例39a M-CKPSJaSAR^aRH-羥基-六氫·呋喃并[3,2-叫呋喃-3-基硫基】-乙醯基}-截短素 (DMSO-d6) ： 6.15,5.07,5.03 (3xm,H19,H2〇,H21), 5.55 (d, 1H, Η! 4, J=8.3Hz), 4.85 (d, 1H, 6r-OH, J= 6.4Hz), 4.5 (d, 1H, 11-OH, J=6.1Hz), 3.65-4.45 (m, Hr 3a', H-6a', H-2', H-5', H-6'), 3.3-3.45 (MH-5'} Η!!, H-3·，H2 2 )，1.35, 1.05 (2xs，（CH3 h 5，（CH3 \ 8 )，0.8, 0.62 (2xd，(CH3)16，(CH3)17，J=6.9Hz) 實例39b l4-0_{[(3R,3aS,6R，6aR)-6-羥基-六氫-呋喃并[3,2-b]*1夫喃-3-基硫基】-乙酿基}-截短素 (DMSO-d6) : 6.15,5.06,5.03 (3xm，H19，H2〇，H21)， 5.55 (d, 1H, Hi 4, J=8.3Hz), 4.8 (d, 1H, 6'-OH, J= 5.7Hz), 4.5 (d, 1H, 11-OH, J=6.1Hz), 3.7-4.45 (m, H-3a'，H-6a'，H-2·，H-5·，H-6')，3.2-3.5 (MH-5'，l5 H-3，， H22)，1.35, 1.05 (2xs，（CHJ 5,（CHA 8)，0.8, 0.62， (2xd，(CH3)16，(CH3)17，J=6.8Hz) 實例39c 14-0-([(3S，3aS，6S，6aR)-6-羥基-六氫-咬喃并[3,2-(CH3)18jJ=6.8Hz) Example 38c 14-0-{[(3S,3aS,6R,6aR)-6-((R)-Amino-3-indolyl-butanylamino)-hexahydro-indole Methyl [3,2-b]furan-3-ylthio]-ethenyl}- truncated as hydrochloride (DMSO-d6) : 8.4 (d, 1H, NH, J = 7.8 Hz ), 8.1 (bs, 3H, NH3 + ), 6.15, 5.06, 5.02 (3xm, 呒9, H20, H2, ), 5.55 (d, 1H, 8.2Hz, 4), 4.6, 4.5 (2xm, 2H,, H3a', H6a,), 3.6-4.4 (m, 5H, H-2', H-5', H-6'), 3.3-3.5 (m, 4H, ^ l, H-3', H2 2) , 1.35, 1.05 (2xs, (CH3 \ 5, (CH3), 8 ), 0.94. 0.90 (d, (CH3 )2 CH, J=6.8Hz), 0.8, 0.62 (2xd, (CH3 &gt;! 6, (CH3)17, J=6.8 Hz)_ Example 39a M-CKPSJaSAR^aRH-hydroxy-hexahydrofuran [3,2-called furan-3-ylthio]-ethenyl}- truncated ( DMSO-d6): 6.15, 5.07, 5.03 (3xm, H19, H2〇, H21), 5.55 (d, 1H, Η! 4, J=8.3Hz), 4.85 (d, 1H, 6r-OH, J= 6.4 Hz), 4.5 (d, 1H, 11-OH, J=6.1Hz), 3.65-4.45 (m, Hr 3a', H-6a', H-2', H-5', H-6'), 3.3-3.45 (MH-5'} Η!!, H-3·, H2 2 ), 1.35, 1.05 (2xs, (CH3 h 5, (CH3 \ 8 ), 0.8, 0.62 (2xd, (CH3)16, (CH3) 17, J = 6.9 Hz) Example 39b l4-0_{[(3R, 3aS, 6R 6aR)-6-Hydroxy-hexahydro-furo[3,2-b]*1-pentan-3-ylthio]-ethidyl}- truncated (DMSO-d6): 6.15,5.06,5.03 (3xm, H19, H2〇, H21), 5.55 (d, 1H, Hi 4, J=8.3Hz), 4.8 (d, 1H, 6'-OH, J= 5.7Hz), 4.5 (d, 1H, 11 -OH, J=6.1Hz), 3.7-4.45 (m, H-3a', H-6a', H-2·, H-5·, H-6'), 3.2-3.5 (MH-5', L5 H-3,, H22), 1.35, 1.05 (2xs, (CHJ 5, (CHA 8), 0.8, 0.62, (2xd, (CH3)16, (CH3)17, J=6.8Hz) Example 39c 14- 0-([(3S,3aS,6S,6aR)-6-hydroxy-hexahydro-tridentate[3,2-

84364 -51 - 1331916 b]呋喃-3·基硫基卜乙醯基}-截短素 (DMSO-d6) : 6.1，5.07,5.02(3xm，H19，H2G，H21): 5.55(d，lH，H14，J=8_3Hz)，5_2(d，lH，6’-OH)，3.55-4.55 (m，11-OH，H-3a，，H-6a'，H2'，H-5，，H-6，)，3.3-3.45 (m, H}!, H-3', H2 2), 1.35, 1.05 (2xs, (CH3 )l5, _(CH3 )i 8，0.8, 0.62 (2xd，（CH3 h 6，（CHA 7，J=6.8Hz) 於另一方面，本發明係提供14_〇-傳基-或酮基）_(雜環基_硫 基甲基羰基）-截短侧耳素，其中雜環基為4至8個環員，較佳 為5至7個環員之脂族環，包含一個氮作為雜原子，例如下 式化合物84364 -51 - 1331916 b]furan-3-ylthiopyridinyl}- truncated hormone (DMSO-d6): 6.1, 5.07, 5.02 (3xm, H19, H2G, H21): 5.55 (d, lH, H14, J=8_3Hz), 5_2(d,lH,6'-OH), 3.55-4.55 (m,11-OH,H-3a,,H-6a',H2',H-5,,H-6 ,),3.3-3.45 (m, H}!, H-3', H2 2), 1.35, 1.05 (2xs, (CH3)l5, _(CH3)i 8,0.8, 0.62 (2xd,(CH3 h 6 (CHA 7, J = 6.8 Hz) In another aspect, the present invention provides 14_〇-transyl- or keto)-(heterocyclyl-thiomethylcarbonyl)-pleuromutilin, wherein The ring group is an aliphatic ring of 4 to 8 ring members, preferably 5 to 7 ring members, and contains a nitrogen as a hetero atom, such as a compound of the formula

其中among them

Rid具有如上文定義之R1A之意義，Rid has the meaning of R1A as defined above,

Kd具有如上文定義之R2A之意義， ^4D具有如上文定義之hA之意義， 虚線具有如上文定義之意義，及 反3〇為4至8個環員之脂族雜環基，且包含一個氮原子作為雜 原子’或（C4 - s)環燒基’該雜環基或環規基係被超基气自同基 取代。 在式ID化合物中，較佳情況是 • Ri d為氫或氘， 84364 -52- R2 D為氫或氣， 虛線不存在（單鍵）， * R3D係如上文定義，例如雜環基具有較佳為5至7個環員 ’例如雜環基係經由碳鍵連接至式ID化合物中之硫；譬 如羥，四虱吡咯、羥基六氫吡啶、酮基-全氫-氮七圜基 及環烷基較佳為（q _ d環烷基，例如環戊酮基， R4 D為氫或I， . 例如，包括14-0伤基.或_基_雜環基_硫基甲基羰基截短例 耳素，其牛雜環基為4至8個環員之脂族環，較佳為…個 2含一個氮作為雜原+，其係選自包括例如包含截短側 耳素，其係選自包括下式化合物Kd has the meaning of R2A as defined above, ^4D has the meaning of hA as defined above, the dotted line has the meaning as defined above, and the anti-3〇 is an aliphatic heterocyclic group of 4 to 8 ring members, and comprises A nitrogen atom as a hetero atom 'or (C4 - s) cycloalkyl group' is substituted with a hetero group gas from a homo group. In the compound of the formula ID, it is preferred that • Ri d is hydrogen or deuterium, 84364 -52- R2 D is hydrogen or gas, and the dotted line is absent (single bond), * R3D is as defined above, for example, heterocyclic group has Preferably, 5 to 7 ring members, such as heterocyclic groups, are attached to the sulfur of the compound of formula ID via a carbon bond; for example, hydroxy, tetrapyrrole, hydroxyhexahydropyridine, keto-perhydro-nitrogen-7-yl and ring The alkyl group is preferably (q _ d cycloalkyl, such as cyclopentanone, R 4 D is hydrogen or I, for example, including 14-0, or _yl-heterocyclyl-thiomethylcarbonyl a short ear, wherein the bovine heterocyclic group is an aliphatic ring of 4 to 8 ring members, preferably 2 contains a nitrogen as a heterologous +, which is selected from, for example, including pleuromutilin, which is Selected from compounds including the following formula

00

其中REf如表5中所列示者。表5之化合物係為式1£化合 物，惟貫例41化合物除外，其係為式^化合物。所^及 根據例如類似如實例中所述之方法所獲得之化 :Where REf is as listed in Table 5. The compound of Table 5 is a compound of Formula 1 except that the compound of Example 41 is a compound of the formula. And according to, for example, a method similar to that described in the examples:

NMR數據亦顯示於表5中： 。物，其H 84364 -53- 1331916 表5 Rex HO ir 實例40 14-0-[(3-R*-羥基四氫吡咯-4-(R*)基）-硫基乙 醯基I-截短素與14-0-丨(3-S*-瘦基四氫吡咯-4-(s*)基）-硫基-乙醯基]-截短素，呈鹽酸鹽形式 (非對映異構混合物） (d-6-DMSO)： 9.4, 9.65 (2xb, 2H, NH2 + ), 3.6, 3.2 (2xm, 4H, CH2NCH2), 4.45 (m, 1H, CHO), 3.45-3.32 (m, 3H, Hi i H22), 3.95 (m, 1H, CHS), 1.18,1.45 (2xs, (CH3), 5, (CH3)! 8), 0.75, 0.88 (2xd, (CH3 ^ 6, (CH3 h 7, J=5.4Hz 0.98) Rex OH σ H 實例41 2,2,4-三氘-14-0-[((3_(S*)-羥基六氫吡啶-4-(S*)-基)硫基)-乙醯基】截短素，呈氣化氘形式 (d-6-DMSO, 350K) ： 8.05 (b, 3H, NH3 +), 4.25-4.1 (m, 3H, CH2N, NHCHC=0), 3.75 (m, 1H, CHO), 3.45-3.32 (m, 3H, H!! H22), 2.89 (m, 1HS CHS), 1.18, 1.45 (2xs, (CH3 )2 5, (CH3)! g), 0.9 (m, 6H, CH(CH3 )2), 0.75, 0.88 (2xd, (CH3 h 6，（CH3 )丨 7，J=5.4Hz 0.98).三環狀部份 基團之2,2'-與4-質子信號係在該光譜中消失 。質量光譜（MS) : m/e : 496 Rex 實例42 A 14-0-[(3R*-樂基六氫吡啶-4_(R*)基）-硫基-乙醯 :基I截短素，呈鹽酸鹽形式+ 14-0-[(3S*-羥基 六氫吡啶_4_(S*)基)-硫基-乙醯基】截短素，呈 鹽酸鹽形式 (d-6-DMSO, 350K) ： 8.05 (b, 3H, NH3 + ), 4.25-4. l(m, 3H, CH2N, NHCHC=0), 3.75 (m, 1H, CHO), 3.45-3.32 (m, 3H, j H22), 2.89 (m, 1H, CHS), 1.18,1.45 (2xSj (CH3 5, (CH3 )t 8), 0.9 (m, 6H, CH(CH3 )2), 0.75, 0.88 (2xd, (CH3 h 6，(CH3 h 7，J=5_4Hz 0.98)NMR data is also shown in Table 5: H 84364 -53-1331916 Table 5 Rex HO ir Example 40 14-0-[(3-R*-Hydroxytetrahydropyrrole-4-(R*)))-thioethenyl I- Truncated And 14-0-indole (3-S*-thinyltetrahydropyrrole-4-(s*)yl)-thio-ethenyl]- truncated as a hydrochloride salt (diastereomeric (d-6-DMSO): 9.4, 9.65 (2xb, 2H, NH2 + ), 3.6, 3.2 (2xm, 4H, CH2NCH2), 4.45 (m, 1H, CHO), 3.45-3.32 (m, 3H , Hi i H22), 3.95 (m, 1H, CHS), 1.18, 1.45 (2xs, (CH3), 5, (CH3)! 8), 0.75, 0.88 (2xd, (CH3 ^ 6, (CH3 h 7, 7, J = 5.4 Hz 0.98) Rex OH σ H Example 41 2,2,4-trimethyl-14-0-[((3_(S*)-hydroxyhexahydropyridin-4-(S*)-yl)thio) )- acetyl group] truncated, in the form of gasified hydrazine (d-6-DMSO, 350K): 8.05 (b, 3H, NH3 +), 4.25-4.1 (m, 3H, CH2N, NHCHC=0), 3.75 (m, 1H, CHO), 3.45-3.32 (m, 3H, H!! H22), 2.89 (m, 1HS CHS), 1.18, 1.45 (2xs, (CH3)2 5, (CH3)! g), 0.9 (m, 6H, CH(CH3)2), 0.75, 0.88 (2xd, (CH3 h 6,(CH3)丨7, J=5.4Hz 0.98). 2,2'- of the tricyclic moiety And the 4-proton signal line disappeared in this spectrum. Mass Spectrum (MS): m/e: 496 Rex Example 42 A 14- 0-[(3R*-Letylhexahydropyridine-4_(R*)))-thio-acetamidine: group I truncation, in the form of hydrochloride + 14-0-[(3S*-hydroxy six Hydropyridine _4_(S*)yl)-thio-ethenyl] truncation, in the form of the hydrochloride (d-6-DMSO, 350K): 8.05 (b, 3H, NH3 + ), 4.25-4 l(m, 3H, CH2N, NHCHC=0), 3.75 (m, 1H, CHO), 3.45-3.32 (m, 3H, j H22), 2.89 (m, 1H, CHS), 1.18, 1.45 (2xSj ( CH3 5, (CH3 )t 8), 0.9 (m, 6H, CH(CH3 )2), 0.75, 0.88 (2xd, (CH3 h 6, (CH3 h 7, J=5_4Hz 0.98)

84364 • 54- ^3191684364 • 54- ^31916

實例43 14_0-丨((一氮七園烷-2-酮-4_〇R/S)-基）-硫基乙醯 基)】-截短素 (d6-DMSO) : 6.15,5.1 (2xm，H19，H20，H2i)，5.52(d， 1H, J=5.2Hz, Η! 4), 3.4 (m, 1H, !), 3.3 (m, 2H, H2 2), 3.1 (m, 2H, SCH，CHN)，1.18, 1.45 (2xs，(CHA 5, (CH3 )t 8), 0.75,0.88 (2xd, (CH3 \ 6, (CH3), 7, J=5.4Hz) 實例44 14-〇-{[(3-嗣基-環戊-(R/S)-基)-硫基】-乙醯基}-截短素 (CDC13) : 6.45, 5.35, 5.2 (3xm, Η! 9，H2 〇，H2 i )，5.8 (d, 1H, H! 4, J=8.4Hz), 3.6 (m, 1H, SCH), 3.35 (m, 1H, ll-OH)，AB-系統（~=3.25，vb=3.17,2H，H22，J= 14.8Hz), 2.65 (m, 1/2H, H-2a'), 2.6 (m, 1/2H, H-2a'), 1.45,1.18 (2xs，(CH3 h 5，(CH3 h 8), 0.9, 0.75 (2xd， (CH3 5, (CH3 7, J=6.8Hz) ____ 本發明戶斤提供之新穎化合物’包括在表1至表5中所列示 义化合物’其化學式’及式Ia、Ib、Ic、1〇、&amp;、〗,以及 δ物’係於本文稱為&quot;（根據）本發明之新賴化合物&quot;。&quot;胺 基酸之殘基&quot;，無論何時被定義於任一種本發明之新穎化合 物中，係包括胺基酸部份，例如包括天然與合成胺基酸， 例如纈胺酸，及如本文中定義之其他胺基酸，最佳為纈胺 酸，其係為若來自羧酸基之羥基被分裂時仍然留下者，例 如在纈胺酸[HO-CO-CHCNH^CiKCH3)2]之情況下，殘基為_c〇 CH(NH2)-CH(CH3)2。 在本發明之新穎化合物中，各單獨定義之取代基可為較佳 取代基，例如互相獨立之經定義取代基。 84364 -55- 1331916Example 43 14_0-丨((Nitrogen-7-octanyl-2-one-4_〇R/S)-yl)-thioethenyl)]- truncated (d6-DMSO): 6.15,5.1 (2xm , H19, H20, H2i), 5.52 (d, 1H, J=5.2Hz, Η! 4), 3.4 (m, 1H, !), 3.3 (m, 2H, H2 2), 3.1 (m, 2H, SCH , CHN), 1.18, 1.45 (2xs, (CHA 5, (CH3)t 8), 0.75, 0.88 (2xd, (CH3 \ 6, (CH3), 7, J=5.4Hz) Example 44 14-〇-{ [(3-Mercapto-cyclopentyl-(R/S)-yl)-thio]-ethenyl}- truncated (CDC13): 6.45, 5.35, 5.2 (3xm, Η! 9, H2 〇, H2 i ), 5.8 (d, 1H, H! 4, J=8.4Hz), 3.6 (m, 1H, SCH), 3.35 (m, 1H, ll-OH), AB-system (~=3.25, vb= 3.17, 2H, H22, J = 14.8 Hz), 2.65 (m, 1/2H, H-2a'), 2.6 (m, 1/2H, H-2a'), 1.45, 1.18 (2xs, (CH3 h 5 , (CH3 h 8), 0.9, 0.75 (2xd, (CH3 5, (CH3 7, J=6.8Hz) ____ The novel compound provided by the present invention 'includes the listed compounds listed in Tables 1 to 5' Its chemical formula 'and formulas Ia, Ib, Ic, 1〇, &, 〗, and δ' are referred to herein as &quot;(according to) the novel compounds of the present invention&quot;&quot;&quot;, whenever defined in any of this The novel compounds include amino acid moieties, including, for example, natural and synthetic amino acids, such as valine acid, and other amino acids as defined herein, preferably valine, if When the hydroxyl group of the carboxylic acid group is cleaved, for example, in the case of valine acid [HO-CO-CHCNH^CiKCH3)2], the residue is _c〇CH(NH2)-CH(CH3)2. In the novel compounds of the present invention, each of the individually defined substituents may be a preferred substituent, for example, a substituent which is independent of each other. 84364 - 55 - 1331916

物形式。Form of matter.

新穎化合物， ;且反 丁烯一酸、萘-1，5_磺酸、磷酸、酒石酸、檸榼 氯酸，較佳為鹽酸。呈自由態形式之本發明 可被轉化成其呈鹽形式之相應化合物； &lt;亦然。呈自由態形式或呈鹽形式及呈溶劑合物形式之本 發明新穎化合物，可被轉化成其呈自由態形式或呈鹽形式 、呈未溶劑化合形式之相應化合物；且反之亦然。 本發明之新穎化合物可以其異構物及混合物形式存在；·例 如光學異構物，非對映異構物，順式_、反式構形異構物 。本發明之化合物可例如含有不對稱碳原子，且因此可以 其非對映異構物及混合物形式存在，例如外消旋物。例如 ’本發明之新穎化合物可包含胺基酸之殘基。在此種胺基 fee殘基中’胺基所連接之碳原子可為不對稱碳原子，且所 連接之胺基可因此呈R-或S-組態》本發明之新穎化合物可包 含環烷基’例如連接至硫基，該環烷基可進一步被取代， 且該取代基可以順式或以反式構形存在。例如，硫基所連 接之環燒基之碳原子可為不對稱’例如，若該環燒基係進 一步被取代，且連接至該環烷基之取代基可呈R_或呈s_組態 84364 -56· 基例明之新穎化合物亦可包含肟基。連接至亞胺 、=各可王同側-或呈對側_組態。異構混合物可按適當 私+ 頒似€用艾万法分離，以獲得純異構 % β本發明係包括呈弘 ,^ 二k ··* Κ構形式與呈任何異構混合物之 t發明新顆化合物。本發明亦包括本發明新類化合物之互 又異構物，在此種互變異構物可存在之情況中。 、文中所述（任何化合物’例如本發明之新穎化合物，可 々適田万式I成’例如，根據例如習用方法例如類似方 式，或按本文所指定之方式。 ;另方面，本發明係提供一種製造下式化合物之方法A novel compound, and a compound of n-butenoic acid, naphthalene-1,5-sulfonic acid, phosphoric acid, tartaric acid or citrate, preferably hydrochloric acid. The present invention in its free form can be converted to its corresponding compound in the form of a salt; &lt;also. The novel compounds of the present invention in free form or in the form of a salt and in the form of a solvate can be converted to the corresponding compound in its free form or in the form of a salt, in unsolvated form; and vice versa. The novel compounds of the present invention may exist in the form of their isomers and mixtures; for example, optical isomers, diastereomers, cis-, trans-configuration isomers. The compounds of the invention may, for example, contain asymmetric carbon atoms and, therefore, may exist as diastereomers and mixtures thereof, such as racemates. For example, the novel compound of the present invention may comprise a residue of an amino acid. In such an amine fee residue, the carbon atom to which the amine group is attached may be an asymmetric carbon atom, and the attached amine group may thus be in the R- or S-configuration. The novel compounds of the present invention may comprise naphthenes. The group 'is, for example, attached to a thio group which may be further substituted, and which may be present in cis or in a trans configuration. For example, the carbon atom of the cycloalkyl group to which the thio group is attached may be asymmetric 'for example, if the cycloalkyl group is further substituted, and the substituent attached to the cycloalkyl group may be in the form of R_ or in the s_ configuration 84364 -56· The novel compounds of the basic examples may also contain a mercapto group. Connect to the imine, = each side of the same side - or in the opposite side _ configuration. The isomeric mixture can be separated by the appropriate method to obtain pure isomeric %. The present invention includes the invention of the invention, including the composition of the invention, and the formation of any heterogeneous mixture. a compound. The invention also includes the reciprocal isomers of the novel classes of the invention, in the presence of such tautomers. As described herein (any compound 'e.g., a novel compound of the present invention, can be formulated, for example, according to conventional methods, for example, in a similar manner, or as specified herein. In addition, the present invention provides Method for producing a compound of the formula

其中 R1P具有如上文定義之Ria之意義， R2P具有如上文定義之R2A之意義， R3P具有如上文定義之之意義， 虛線具有如上文定義之意義，及Wherein R1P has the meaning of Ria as defined above, R2P has the meaning of R2A as defined above, R3P has the meaning as defined above, the dashed line has the meaning as defined above, and

Rp具有如申請專利範圍第6至u項中任一項所陳述之意義 其包括以下步驟 84364 •57- 1331916 使下式化合物Rp has the meaning as set forth in any one of claims 6 to 5, which includes the following steps: 84364 • 57- 1331916

其中R1P與I^p均如上文定義，且虛線具有如上文定義之 意義， - 與硫脲立應，接著還原’以獲得下式化合物Wherein R1P and I^p are as defined above, and the dotted line has the meaning as defined above, - reacts with thiourea, and then decreases to obtain a compound of the formula

其中R1P與R2P均如上文定義， b.使步驟a.中獲得之式lip化合物，與下式化合物反應Wherein R1P and R2P are as defined above, b. reacting the lip compound obtained in step a. with a compound of the formula

Rp-H 其中RP係如上文定義，呈反應形式，例如甲烷磺酸根或 甲苯磺酸根，視情況呈經保護形式， 以獲得式Ip化合物（意即本發明之新穎化合物），或獲得式 Ip化合物之預先形式， c.視情況進一步使步驟b.中獲得之預先形式反應，以獲得 式Ip化合物，例如引進氘，以獲得式Ip化合物，其中取代 基均如上文定義， 84364 -58 - 及 d·使步騾b.或步驟c.中獲得之式j化a - ρΊϋ D物’自反應混合物單 離。 心係為 '經取代之（C4-8)環烷基， •經取代之苯基， _經取代之脂族雜環基，具有4至8 卜 個每具’並包含1或2個 氮原子作為雜原子， 燒基’破（經取代）胺基取代， •烷基，被雜環基取代，或 -經取代之雙環狀脂族雜環基， 個氧雜原子， 於“中包含5個環員及一 例如在本發明新顆截短側耳素中包含％之意義 清專利範圍第6至11項中所陳述者。 本發明所提供之方法可例如 束去am山 以類似本又所引用之任何專利 參考資料中所陳述之方法推 j寻旧 万，去進仃，例如類似本文所引用之春 利又獻中所述化合物之製 &lt; 專 % I 法譬如在 W0〇l〇_5、 及 W00222580 中，&lt; 如太 + + &lt; 04414 甲 本又中所述者。於本文中引用夕阱古 專利參考資料係被引進 斤有 圍與取代λ之以 尤其是關於巾請專利範 製造方Γ ,包括取代基之較佳意義，及關於Rp-H wherein RP is as defined above, in a reactive form, such as methanesulfonate or tosylate, optionally in protected form, to obtain a compound of formula Ip (meaning a novel compound of the invention), or to obtain a compound of formula Ip a pre-form, c. optionally reacting the pre-form obtained in step b. to obtain a compound of formula Ip, for example, a hydrazine, to obtain a compound of formula Ip, wherein the substituents are as defined above, 84364-58- and d • Let the formula a obtained in step b. or step c. a - ρ Ίϋ D 'single from the reaction mixture. The heart is a 'substituted C10-8 cycloalkyl group, a substituted phenyl group, a substituted aliphatic heterocyclic group, having 4 to 8 groups each containing '1 or 2 nitrogen atoms As a hetero atom, a pyridyl-substituted (substituted) amine group, an alkyl group, a heterocyclic group, or a substituted bicyclic aliphatic heterocyclic group, an oxygen hetero atom, a ring member and a person as set forth in, for example, in the novel pleuromutilin of the present invention, wherein the method of the present invention can be carried out, for example, by bundling the am mountain to resemble the present. Any of the patented references cited in the reference to the old method, to go to the sputum, for example, similar to the reference cited in this article, the system of the compound described in the article &lt; Special % I method, such as at W0〇l〇_ 5, and W00222580, &lt;如太+ + &lt; 04414 A is also described in the above. In this article, the reference to the Xishou ancient patent reference material was introduced to replace the λ and especially the patent for the towel. Fan manufacturing, including the preferred meaning of the substituent, and

:發明之截短侧耳素包括具有式4 本發明之截短側耳争包括+ ^ H 截短側耳素，例 η &amp; #本發明之 種截短側耳素，或本發明不同截短側 84364 •59- 1331916 耳素之組合。 · 吾人已發現本發明之新穎化合物，包括式。化合物，在類 似適應徵上，顯示類似截短側耳素之藥理學活性，如在 W00109095、W〇〇2〇4414 及 w〇〇22258〇 中所述者例如在‘ 麵麵、W002044l4及w〇〇22258〇中戶斤述之類似試驗系= 中’此外為在本文中所述之讀玄 下H工Λ驗系統中。因此，式Ip化合 可作為醫藥使用。 於另万面’本發明係提供式Ip化合物作為醫藥使用，較 佳係作為抗微生物劑，譬如抗生素，及作為抗厭氧劑，包 括作為醫藥，用於治療藉由分枝捍菌屬譬如結 所媒介之疾病。 _ 於另-方面，本發明係提供式Ip化合物於藥劑製備上之用 途:該樂劑係用於治療微生物疾病，例如藉由細菌所媒介 屬、八枝ϋ例如選自葡萄球菌屬、鏈球菌屬、腸球.菌 如結核分枝捍菌；及藉由枝原體屬、 衣原體屬及必須厭氧菌所媒介之疾病。 例t另、万本發明係提供一種治療微生物疾病之方法， 例如精由細逵所媒j i '、 、鐘… 菌例如選自葡萄球菌屬 鏈球因屬、腸球菌屬、分枝桿菌屬，例如4分 ，及藉由枝原體屬、衣原體屬及、干菌 ，哕女土肩厭虱菌所媒介之疾病 新：:：要此種治療之病患投予有效量之本發明 二化』，例如包括式,化合物；例如鳴組合物之形 防 冶療作業包括治療與預 84364 1331916 對此種治療而言，適當劑量當然係依例如所採用本發明化 合物《化學性質與藥物動力學數據、個別宿主、投藥模式 及被治療症狀之性質與嚴重性而改變。但是，一般而士， 在：大哺乳為物，例如人類中’為獲得令人滿意：結：： ::::之曰服劑量為在約〇.〇5克至約5〇克範圍之本發明新穎 H可合宜地以例如—天高達四次之分離劑量投予。 屬量適用於以本發明之截短側耳素治療藉由分枝桿菌 屬所媒介之疾病。 丁田 、：發明之新顆化合物可藉任何習用途徑投予，例如 』如包括鼻、面頰、直腸、口服投藥；以 式，例如包括靜脈内、肌内' ，二 例如包格皮上、鼻内、氣J 4以局部方式， 塗覆片，…、 樂；例如呈經塗覆或未經 說瓶、小破瓶之形&lt;，呈乳暮、=〈形式’例如呈安 '泡沐物、町劑…、滴；：糊劑、吸入器粉-末 Q m /罔劑、喷露逾丨I + _L. 形式。_似者吾.高ffl认士改 ^式’或呈栓劑 硕似考篁適用於本發明截短側 屬所媒介疾病中乏浐莖...&amp; '、在藉由分枝桿菌 屄病中ϋ又樂，惟局部投藥除外。 本發明之新穎化合物可以藥學上可 如酸加成鹽或金屬鹽；或呈自由 “ 3式投藥’例 物形式。呈睡形式之太菸Β日、〜/ A，硯情況呈溶劑合 王现形式之本發明新穎化合物， 形式之本發明新類化合物相同之活性級次與呈自由態 :::式。類似考量適用於本發明截短:耳溶劑 柃菌屬所媒介疾病中之投藥。 耳素在藉由分枝 本發明之新穎化合物可單獨 汗用或多種其他醫藥活性 84364 1331916 劑，使用於根據本發明之醫藥治療。此種其他醫藥活性劑 ，例如包括其他抗微生物劑，例如包括抗生素，例如頭孢 菌素、青黴素、紅黴素、四環素。 類似考量適用於本發明截短側耳素在藉由分枝桿菌屬所媒 介疾病之使用上，但適當之其他醫藥活性劑，包括已知在 藉由分枝桿菌屬所媒介疾病之治療上，具有活性之藥劑， 譬如利福平（Rifampicin®)、鏈黴素（Strept〇mycin®)、乙杉布醇 (Ethambutol)®) ' 吡畊蜜得(Pyrizinamid&lt;g))。 _ ，且 包括固疋組合，其中兩種或多種醫藥活性劑係在相同 配方中，套件，其中在個別配方中之兩種或多種醫藥活性 劑，係以相同包裝銷售，例如伴隨著共同投藥之說明書； 及自由組合，其中醫藥活性劑係.個別地包裝，但給予同時 或相繼投藥之說明書。 、另方面本發明係提供一種醫藥組合物，其包含本 明之新穎化合物’例如式Ip化合物，伴隨著至少一種醫藥賦 形劑，例士口適當载劑A /或稀釋冑，例如包括填料、黏合劑 、崩解劑、流動調節劑、潤滑劑、糖類與增甜劑' 芳香劑 方腐d安定劑、潤濕劑及/或乳化劑、增溶劑、調節与 透壓用及/或緩衝劑；例如進一步包含另一種醫藥活必 劑。 包含本發明截短侧耳素以在藉由分枝捍菌屬所媒介之疾; 上用讀藥之醫藥組合物，彳包含如上述之類似賦形劑。 ;方面本發明係提供__種醫藥組合物，其包含本$ 明之截短側耳素’伴隨著至少一種醫藥賦形劑，、且進… 84364 •62- 1331916 包含另一種可用於治療分枝桿菌屬，例如結核分枝桿菌感 染之醫藥活性劑，譬如利福平(Rifampicin® )、鏈黴素（Streptomycin®) 、乙杉布醇(Ethambutol)®)、p比 p井蜜得（Pyrizinamid®)。 此種組合物可根據（例如類似）習用方法製造，例如經由混 合、粒化、塗覆、溶解或凍乾方法。單位劑量形式可含有 例如約0.5毫克至約1500毫克，譬如1毫克至約500毫克。 本發明之截短側耳素在藉由結核分枝桿菌所媒介疾病上之 投藥，可以如利福平或鏈黴素之類似模式與類似劑量投藥、 本發明之截短側耳素較佳係選自包括式I-US4278674化合物 、式I-EP0153277 化合物、式I-W00109095 化合物、式I-W00204414 化合物、式I-W00222580化合物、表I化合物、式Ib化合物或 式ID化合物； 例如包括 -式I-提耳目林(Tiamulin)化合物 · -式I-華臬目林(Valnemulin)化合物，例如呈鹽酸鹽形式； -下式化合物The pleuromutilin of the invention comprises a truncated side ear of the invention comprising the formula: + ^ H pleuromutilin, for example η &amp;# pleuromutilin of the invention, or different truncated side 84364 of the invention • 59- 1331916 Combination of ear. · We have discovered novel compounds of the invention, including formulas. The compound, on similar indications, shows pharmacological activity similar to pleuromutilin, as described in W00109095, W〇〇2〇4414 and w〇〇22258〇, for example in 'face, W002044l4 and w〇〇 The similar test system of 22258 〇中中金=中中' is also included in the reading system of H. Therefore, the compound of the formula Ip can be used as a medicine. In the present invention, the present invention provides a compound of the formula Ip for use as a pharmaceutical, preferably as an antimicrobial agent, such as an antibiotic, and as an anti-anaerobic agent, including as a medicine, for treatment by a genus of the genus Mycobacterium. The disease of the media. In a further aspect, the invention provides the use of a compound of formula Ip for the preparation of a medicament for the treatment of a microbial disorder, for example by a bacterium of the genus Bacillus, for example, from the group consisting of Staphylococcus, Streptococcus Intestinal bacillus, such as Mycobacterium tuberculosis; and diseases mediated by Mycoplasma, Chlamydia, and essential anaerobic bacteria. The invention provides a method for treating a microbial disease, for example, a fine medium, such as a bacterium belonging to the genus Staphylococcus, Enterococcus, Mycobacterium, for example, 4 points, and diseases mediated by Mycoplasma, Chlamydia, and dried bacterium, scorpion scorpion scorpion sputum new::: The patient to be treated for this treatment is given an effective amount of the invention. For example, including formulas, compounds; for example, the composition of the anti-allergic treatment includes treatment and pre-84364 1331916 for such treatment, the appropriate dosage is, of course, based on, for example, the compounds of the invention employed, "chemical and pharmacokinetic data, individual The host, the mode of administration, and the nature and severity of the condition being treated vary. However, in general, in the case of large breastfeeding, for example, in humans, 'for satisfactory: knot:::::, the dose is from about 5 gram to about 5 gram. The novel invention H can conveniently be administered, for example, in divided doses up to four times a day. The genus is suitable for treating a disease mediated by Mycobacterium by the pleuromutilin of the present invention. Ding Tian, the new compound of the invention can be administered by any conventional means, such as "including nasal, cheek, rectal, oral administration; for example, including intravenous, intramuscular", for example, on the skin, intranasal, intranasal , gas J 4 in a partial manner, coated sheet, ..., music; for example, coated or unspoken, small broken bottle shape &lt;, is a chyle, = <form' such as An's bubble , town agent ..., drip;: paste, inhaler powder - end Q m / sputum, spray 丨 丨 I + _L. form. _似者吾.High ffl 士士改^式' or is a suppository 硕 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁 篁Lieutenant is happy, except for local medication. The novel compound of the present invention may be pharmaceutically acceptable as an acid addition salt or a metal salt; or in the form of a free "3 type administration". It is too smoky in the form of sleep, ~/A, and the case is a solvent. A novel compound of the invention in the form of a novel class of compounds of the invention having the same activity level and in a free state:::. Similar considerations apply to the truncation of the invention: administration of a disease mediated by the genus Solanum. The invention may be used for the treatment according to the present invention by branching the novel compound of the present invention with a single sweat or a plurality of other pharmaceutically active 84364 1331916 agents. Such other pharmaceutically active agents include, for example, other antimicrobial agents, including, for example, antibiotics. , for example, cephalosporin, penicillin, erythromycin, tetracycline. Similar considerations apply to the use of the pleuromutilin of the present invention in the use of diseases mediated by mycobacteria, but other suitable pharmaceutically active agents, including An active agent for the treatment of diseases mediated by mycobacteria, such as Rifapicin®, Strept〇mycin®, and cedar (Ethambutol)®) 'Pyrizinamid&lt;g). _ and includes a combination of two or more pharmaceutically active agents in the same formulation, a kit, of which two of the individual formulations or A plurality of pharmaceutically active agents are sold in the same package, for example, with instructions for co-administration; and free combinations, wherein the pharmaceutically active agents are individually packaged, but are given instructions for simultaneous or sequential administration. Further, the present invention provides a method. A pharmaceutical composition comprising a novel compound of the present invention, such as a compound of formula Ip, accompanied by at least one pharmaceutical excipient, such as a suitable carrier A / or diluted hydrazine, for example, including fillers, binders, disintegrants, flow regulation Agents, lubricants, saccharides and sweeteners 'aromatics stagnation d stabilizers, wetting agents and / or emulsifiers, solubilizers, conditioning and osmotic pressure and / or buffers; for example, further containing another medical activity The pharmaceutical composition comprising the pleuromutilin of the present invention for mediated by the genus Mycobacterium; the pharmaceutical composition for reading the drug, the sputum comprises a similar excipient as described above; The present invention provides a pharmaceutical composition comprising the pleuromutilin of the present invention accompanied by at least one medical excipient, and ... 84364 • 62-1331916 contains another species useful for treating mycobacteria, for example A pharmaceutically active agent for M. tuberculosis infection, such as Rifapicin®, Streptomycin®, Ethambutol®, and pizizinamid®. The compositions may be made according to conventional methods, for example, by mixing, granulating, coating, dissolving or lyophilizing. The unit dosage form may contain, for example, from about 0.5 mg to about 1500 mg, such as from 1 mg to about 500 mg. The pleuromutilin of the present invention can be administered in a similar manner as rifampicin or streptomycin, and the pleuromutilin of the present invention is preferably selected from the group consisting of diseases mediated by M. tuberculosis. Included are compounds of formula I-US 4278674, compounds of formula I-EP0153277, compounds of formula I-W00109095, compounds of formula I-W00204414, compounds of formula I-W00222580, compounds of formula I, compounds of formula Ib or compounds of formula ID; for example including -form I Tiamulin compound - a compound of formula I - Valnemulin, for example in the form of a hydrochloride; - a compound of the formula

例如呈鹽酸鹽形式； -下式化合物 84364 -63- 1331916For example, in the form of a hydrochloride salt; - a compound of the formula 84364 - 63 - 1331916

例如呈鹽酸鹽形式， -下式化合物For example, in the form of the hydrochloride salt, - a compound of the formula

例如呈鹽酸鹽形式， -下式化合物For example, in the form of the hydrochloride salt, - a compound of the formula

例如呈鹽酸鹽形式， -下式化合物 -64 84364 1331916For example in the form of the hydrochloride salt, - a compound of the formula -64 84364 1331916

H3c/NH3c/N

o ch3o ch3

I-PREF5 例如呈鹽酸鹽形式， -下式化合物I-PREF5 is, for example, in the form of a hydrochloride salt, - a compound of the formula

0 ch3 I-PREF6 例如呈鹽酸鹽形式， -下式化合物0 ch3 I-PREF6 is, for example, in the form of a hydrochloride salt, - a compound of the formula

I-PREF7 及 -以下化合物 -65- 84364 丄331916I-PREF7 and - the following compounds -65- 84364 丄331916

例如呈鹽酸鹽形式。 抵柷分枝桿菌屬菌株例如結核分枝桿菌之活性，可根據下 文一般試驗程序測得： _ 一般試驗程序 其係根據已知及適當遭脂稀釋試驗進行。遭脂係作為受質 使用。在瓊脂固化之前不久，添加不同濃度之淨麻合场 並此入仍為液體之瓊脂團料（根據瓊脂稀釋試驗）中。亦 製備未具有#麻㈣之對照組，以敎”生長能力。 將如此製成〈瓊脂，^固化後，以結核分枝桿菌菌株接種 。在-般培養器中，於3rc下進行培養。使用沾一 :ADC(油酸 '白蛋白、右旋糖、過氧化幻濃化物 (pH 6.71-6.73)作為營養培養基。 取低抑㈣很度(MIC) ’其係為瓊脂中抑制Μ 合物濃度、，其㈣接種後之3週、4週及5週後測定生長《化 二明《截短側耳素顯示抵抗分枝桿菌屬之菌株例如結核 U本：Γ生’因此可用於治療因分枝桿菌屬所造成之 性&quot;重二藥：截短側耳素令人驚訏地甚至具有對於抗藥 可用::::::核分枝桿菌菌株之活性，例如對於使用 。4〈已知醫藥治療具抗藥性之菌株，該醫 84364 -66- 1331916 藥例如異於酸Sr、利福平、鏈黴素。 【實施方式】 於下述實例中，所有溫度均以攝氏度數表示，而未經校正 。使用下列縮寫： BOC ： 第三丁氧羰基 DCC : 二環己基碳化二亞胺 DMF ： Ν,Ν-二曱基甲醯胺 DMSO :二甲亞颯 EDC ： Ν-(3-二曱胺基丙基）-Ν'-乙基碳化二亞胺鹽酸鹽For example in the form of the hydrochloride salt. The activity against a Mycobacterium strain such as M. tuberculosis can be measured according to the following general test procedure: _ General test procedure It is carried out according to known and appropriate lipid dilution tests. The fat is used as a substrate. Shortly before the agar solidification, a different concentration of the net pitting field was added and this was still a liquid agar mass (according to the agar dilution test). A control group not having #麻(四) was also prepared, and the growth ability was obtained. The agar was prepared, and then solidified, and then inoculated with a Mycobacterium tuberculosis strain. In a general culture, culture was carried out at 3 rc. Dip: ADC (oleic acid 'albumin', dextrose, peroxygen concentrate (pH 6.71-6.73) as a nutrient medium. Take low (four) very (MIC) 'the system is agar to inhibit the concentration of the compound (4) After 3 weeks, 4 weeks, and 5 weeks after inoculation, growth was measured. "Chemical Ermectin" shows that the pleuromutilin shows a strain resistant to Mycobacterium, such as tuberculosis U: axillary, so it can be used for the treatment of branching Sexuality caused by Bacillus &quot;heavy drug: pleuromutilin is surprisingly even available for drug resistance:::::: Activity of M. tuberculosis strains, for example for use. 4 < Known medicine For the treatment of drug-resistant strains, the medicine 84364-66-1331916 drugs such as iso-acid Sr, rifampicin, streptomycin. [Embodiment] In the following examples, all temperatures are expressed in degrees Celsius, and not Correction. The following abbreviations are used: BOC : Third butoxycarbonyl DCC: Dicyclohexyl Of carbodiimide DMF: Ν, Ν- two Yue group A Amides DMSO: dimethylsulfoxide Sa EDC: Ν- (3- aminopropyl two Yue) -Ν'- ethylcarbodiimide hydrochloride

EtAc : 醋酸乙酯 EtOH : 乙醇 HOBT ： 1-羥基苯并三唑 MeOH ： 曱醇 MS ： 質量光譜 RT ： 室溫 TBAF ： 敦化四-正-丁基按 TFA : 三氟醋酸 THF ： 四氫吱喃 層析係於矽膠上進行。 製備實例 I.本發明（新穎）截短側耳素之製備 實例Ι-Α 14-0-[(Ν-(3-甲基-2(R)-胺基-丁醯基）-六氫吡啶-3-基）-硫基乙醯基 ]-截短素，呈鹽酸鹽形式 I-AA) 14-0-ITN-B0C-六氫吡啶-3(^)-基）-硫基乙醯基1-截短素 方法1 · 將532毫克22-0-甲苯磺醯基-截短侧耳素添加至217毫克N-B0C-六氫吡啶-3(S)-硫醇與112毫克第三-丁醇鉀在10毫升THF 中之溶液内，將所得混合物攪拌3小時，使所得混合物在EtAc 與鹽水之間分配，使所得有機相脫水乾燥，蒸發溶劑，並 84364 -67- 1331916 使所得之蒸發殘留物接受層析。獲得14-0-[(N-B0C-六氫吡啶_ 3(S)-基）-硫基乙酿基]-截短素。 方法2 : 將1.97克22‘基-截短侧耳素、1.39克N-B0C-3(R)-甲磺醯基氧 基-六氫吡啶及0.12克鈉在50毫升EtOH中之溶液，加熱至90° ，歷經12小時，使溶劑自所得混合物中蒸發，並使蒸發殘 留物接受層析。獲得14-〇[(N-BOC-六氫吡啶-3-基）-硫基乙醯基 ]-截短素。 &quot; 1H-NMR(CDC13)： 6.45, 5.35, 5,2 (3xm, Ul9,R20,U2l), 5.74 (d, 1H, 5,2Hz, 1114)，3.35((1，111，1111，1=5.2叫，处-系統：3.12,3.18，】=14_71^,1122)， 3.2,2.95, 2.65,2.6 (4xm, CH2NCH2), 2.85 (m, 1H, SCH), 1.18,1.45 (2xs, (CH3 )x 5, (CH3 8), 0.75, 0.88 (2xd, (CH3 )j 6, (CH3 )j 7, J=5.4Hz) 甲基-2(R)-胺基-丁醯基）_六氤吡啶_3_基硫某乙 醯基1-截短素，呈镑.酸鹽形式 將280毫克14-0-[(N-B0C-六氫吡啶_3_基）_硫基乙醯基]_截短素 在20宅升CH2 CL與1毫升TFA中之溶液，於室溫下攪拌3〇分 鐘，並使溶劑自所得混合物中蒸發。將所得蒸發殘留物以4〇 毫升CK^Cl2處理’添加55毫克N-甲基-嗎福啉、11〇毫克N-BOC-(R)-纈胺酸及1〇5毫克DCC，並將所得混合物攪拌3小時 °自所得混合物中濾出已沉澱之二環己基脲，並使所得濾 液接受層析。將所得已純化之14&lt;Η(ν_(3-甲基_2(R)_胺基-丁醯 基）-六氫比咬-3-基）_硫基乙醯基]_截短素，以wa在ch2C12中 處理，瘵發溶劑，並將所得之蒸發殘留物以含醚HC1處理。 獲得14-0-[(N-(3-甲基_2(R)-胺基-丁醯基）·六氫吡啶冬基）硫基乙 84364 -68- 1331916 醯基]-截短素，呈鹽酸鹽形式》 _ 1H-NMR (d-6-DMSO, 330K): 6.45, 5.35, 5,2 (3xm，① 9，H2 0，H21 )，5.74 (d， 1H, 5,2Hz, H! 4), 5.45 (d, 1H, NH, J=7.8Hz), 4.1 (m, 1H, NHCHCO), 3.35 (d, 1H，Hu，J=5.2Hz)，ABU^:3.12,3.18，J=14.7Hz，H22)，3.2,2.95,2.65， 2.6 (4xm，CH2 NCH2 )，2.8 (m，1H, SCH)，1 · 18, 1.45 (2xs，（CH3)! 5, (CH3 )】8 )， 0.75,0.88 (2xd, (CH3)l6, (CH37, J=5.4Hz), 0.78.0.84 (2xd, (CH3) 2CH,EtAc : ethyl acetate EtOH : ethanol HOBT : 1-hydroxybenzotriazole MeOH : decyl alcohol MS : mass spectrum RT : room temperature TBAF : Dunhua tetra-n-butyl group TFA : trifluoroacetic acid THF : tetrahydrofuran Chromatography was performed on silica gel. PREPARATION EXAMPLE I. Preparation of the novel (novel) pleuromutilin of the invention Ι-Α 14-0-[(Ν-(3-methyl-2(R)-amino-butanyl)-hexahydropyridine-3- ))-thioethenyl]- truncated, in the form of the hydrochloride salt I-AA) 14-0-ITN-B0C-hexahydropyridine-3(^)-yl)-thioethenyl 1- Truncated Method 1 · Add 532 mg of 22-0-toluenesulfonyl-pleuromutilin to 217 mg of N-B0C-hexahydropyridine-3(S)-thiol and 112 mg of potassium third-butoxide The resulting mixture was stirred for 3 hours in a solution of 10 ml of THF. The mixture was partitioned between Et Et and brine, and the obtained organic phase was dried and evaporated, and the solvent was evaporated, and the obtained evaporation residue was received from 84364-67-1331916 Chromatography. 14-0-[(N-B0C-Hexahydropyridine-3(S)-yl)-thioethyl]-teptin was obtained. Method 2: A solution of 1.97 g of 22'-tide pleuromutilin, 1.39 g of N-B0C-3(R)-methanesulfonyloxy-hexahydropyridine and 0.12 g of sodium in 50 ml of EtOH was heated to The solvent was evaporated from the obtained mixture at 90 ° over 12 hours, and the residue was subjected to chromatography. 14-[[N-BOC-Hexahydropyridin-3-yl)-thioethenyl]- truncated phenol was obtained. &quot; 1H-NMR (CDC13): 6.45, 5.35, 5,2 (3xm, Ul9, R20, U2l), 5.74 (d, 1H, 5, 2Hz, 1114), 3.35 ((1,111,1111,1= 5.2 Call, Department - System: 3.12, 3.18,] = 14_71^, 1122), 3.2, 2.95, 2.65, 2.6 (4xm, CH2NCH2), 2.85 (m, 1H, SCH), 1.18, 1.45 (2xs, (CH3) x 5, (CH3 8), 0.75, 0.88 (2xd, (CH3 )j 6, (CH3 )j 7, J=5.4Hz) methyl-2(R)-amino-butanyl)_hexapyridine _3 _ thiol ethionyl 1-truncated, in the form of pounds acid salt 280 mg 14-0-[(N-B0C-hexahydropyridin-3-yl)-thioethenyl]_ truncated A solution of 20 liters of CH2 CL and 1 ml of TFA was stirred at room temperature for 3 minutes, and the solvent was evaporated from the obtained mixture. The obtained evaporation residue was treated with 4 mL of CK^Cl2. N-methyl-morphine, 11 mg of N-BOC-(R)-proline and 1 5 mg of DCC, and the resulting mixture was stirred for 3 hours. The precipitated dicyclohexyl was filtered off from the mixture. Urea, and the obtained filtrate is subjected to chromatography. The obtained purified 14 &lt; Η (ν_(3-methyl 2 (R)-amino-butyl)-hexahydropyran-3-yl)-thio-ethyl醯基]_ truncation, to wa in ch2C12 After treatment, the solvent was evaporated, and the obtained evaporation residue was treated with ether HCl (1%-[(N-(3-methyl-2(R)-amino-butyl)) hexahydropyridyl ) thioethyl 84364 -68-1331916 fluorenyl]- truncated, in the form of the hydrochloride salt _ 1H-NMR (d-6-DMSO, 330K): 6.45, 5.35, 5,2 (3xm,1 9, H2 0, H21 ), 5.74 (d, 1H, 5, 2Hz, H! 4), 5.45 (d, 1H, NH, J=7.8Hz), 4.1 (m, 1H, NHCHCO), 3.35 (d, 1H, Hu, J=5.2Hz), ABU^: 3.12, 3.18, J=14.7Hz, H22), 3.2, 2.95, 2.65, 2.6 (4xm, CH2 NCH2), 2.8 (m, 1H, SCH), 1 · 18, 1.45 (2xs, (CH3)! 5, (CH3)] 8), 0.75, 0.88 (2xd, (CH3)l6, (CH37, J=5.4Hz), 0.78.0.84 (2xd, (CH3) 2CH,

J=6.8Hz) 實例I-B 14-0-[(N-(3^甲基-2(R)-胺基-丁酿基）·六氫峨唆_3(s)_基）硫基乙酿 基】-2(S)_氟-截短素，呈鹽酸鹽形式J=6.8Hz) Example IB 14-0-[(N-(3^methyl-2(R)-Amino-butyl)-hexahydroindole_3(s)-yl)thio-ethyl Base]-2(S)_fluoro- truncated, in the form of hydrochloride

IBA) 14-0-(甲苯續酿基氧基乙酿基籲,-截短素 於500毫克14-0-(經乙醯基）-2(S)-氟-截短素（參閱，例如Vypld H 等人，C/zem. ; 23, 482 (1983))在 5 毫升 CH2 α2 中之溶液内 ，添加450毫克曱苯磺酸酐與0.21毫升吡啶，並將所得混·合 物於室溫下攪拌4小時。將所得混合物以CH2Cl2稀釋，並二 iNHCi、NaHC〇3水溶液及％〇萃取。使所得有機相脫水乾燥 ，蒸發溶劑，並使蒸發殘留物接受層析。獲得14〇_[甲苯磺 醯基氧基乙醯基]-2⑶-氟-截短素。 ’ 祖迎腿3二甲基_2⑻-胺 二酿基1-2(S)-氟-截短素，呈_酩鹽形式IBA) 14-0-(toluene ethoxylated ethyl ketone, - truncated in 500 mg 14-0-(acetamido)-2(S)-fluoro- truncated (see, for example Vypld H et al., C/zem.; 23, 482 (1983)) In a solution of 5 ml of CH 2 α 2 , 450 mg of toluenesulfonic anhydride and 0.21 ml of pyridine were added, and the resulting mixture was allowed to stand at room temperature. The mixture was stirred for 4 hours, and the resulting mixture was diluted with CH.sub.2Cl.sub.sub.sub.sub.sub.sub.sub.sub.sub. Mercaptoethoxyethyl]-2(3)-fluoro- truncated. ' Zushou leg 3 dimethyl-2(8)-amine di-branched 1-2(S)-fluoro- truncated, in the form of 酩 酩 salt

實例I-C 其係自M-Ο-[甲苯續酿基氧基乙酿基]娜氣-截短素開始， ，似實例IAB)之方法獲得，特徵蓉定數據參閱幻，實例η。 呈鹽酸鹽形式 14-0·[(3-狐基-苯基硫基)-乙醯基】截短素 84364 -69· 1331916 ICA) 14-0-ΙΪ3-胺某-茉基疏某V乙醯基1-截短素 將0.92克鈉與5克3-胺基-硫酚在1〇〇毫升無水EtOH中之溶液 ，於25。下，在小心溫度控制下，添加至21.3克22-0-甲苯磺醯 基-截短側耳素（參閱，例如H· Egger等人，J. Antibiotics 29, 923 (1976))在250毫升乙基甲基酮中之溶液内。將所得混合物於25。 下保持15小時，過濾，並使所得濾液在減壓下濃縮，且使 其接受層析。獲得14-0-[(3·胺基-苯基硫基）-乙醯基]-截短素。 1H-NMR (CDC13) : 0.58 (d，3H，&amp; 6，J=7.2Hz)，0.81 (d，3H，① 7，J=7.3Hz)， 1.02(8,3氏1118)，1.32(8,311，1115)，八8\-系統（2^=1.2，1^=1.88，11133，Example I-C is obtained from the M-Ο-[toluene ethoxylate]-gas-truncated form, as obtained by the method of Example IAB). In the form of the hydrochloride salt 14-0·[(3-foxyl-phenylthio)-ethenyl] truncated serotonin 84364-69· 1331916 ICA) 14-0-ΙΪ3-amine-M-based A solution of 0.92 g of sodium and 5 g of 3-amino-thiophenol in 1 ml of anhydrous EtOH at 25 acetamido-truncated. Next, under careful temperature control, add to 21.3 g of 22-0-toluenesulfonyl-pleuromutilin (see, for example, H. Egger et al., J. Antibiotics 29, 923 (1976)) in 250 ml of ethyl In the solution in methyl ketone. The resulting mixture was at 25. It was kept under 15 hours, filtered, and the filtrate was concentrated under reduced pressure and subjected to chromatography. 14-0-[(3.Amino-phenylthio)-ethinyl]- truncatedin was obtained. 1H-NMR (CDC13): 0.58 (d, 3H, &amp; 6, J = 7.2 Hz), 0.81 (d, 3H, 1, 7, J = 7.3 Hz), 1.02 (8, 3, 1118), 1.32 (8,311) , 1115), eight 8\-system (2^=1.2, 1^=1.88, 11133,

Hi 3b, J=16.1Hz，J=9.1Hz)，2.08 (d，1H，H4, J=2.1Hz)，ABXY-系統 〇a = 2.23, i；B=2.19，H2a，H2b，J=16.2Hz，J=9.1Hz，J=1.8Hz)，2.3 (m，1H，H10)， 3.4 (d，lH，Hn，1==5.981^:), AB-系統（Va=3.81，2&gt;*b=3.89, 2H，H22,J=14.1 Hz), 5.18 (dd, 1H, H20a, J=17.5Hz, J=1.6Hz), 5.29 (dd5 1H, H20b, J=llHz, J= 1.6Hz), 5.51 (d, 1H, H! 4, J=8.3Hz), 6.05 (dd, 1H, Η2 9, J=llHz, J=17.5Hz),; 7·〇 (m，1H,芳族 H)，7.18 (m，2H,芳族 H)，7.3t，1H，芳族 H5, J=8Hz). KB) 14-0-ΙΪ3-胍基-笨基硫某V乙醯基1截短素，呈鹽酸鹽形式 將2.4克14-0-[(3-胺基-苯基硫基）-乙醯基]截短素、1.5克氰胺 及0.44毫升濃HC1在20毫升二氧陸圜中之溶液，於室溫下攪 拌28小時《獲得14-0-[(3-胍基-苯基硫基）-乙醯基]截短素，呈 鹽酸鹽結晶形式。特徵鑒定數據參閱上表。Hi 3b, J=16.1Hz, J=9.1Hz), 2.08 (d, 1H, H4, J=2.1Hz), ABXY-system 〇a = 2.23, i; B=2.19, H2a, H2b, J=16.2Hz , J = 9.1 Hz, J = 1.8 Hz), 2.3 (m, 1H, H10), 3.4 (d, lH, Hn, 1 == 5.981^:), AB-system (Va = 3.81, 2 &gt; * b = 3.89, 2H, H22, J = 14.1 Hz), 5.18 (dd, 1H, H20a, J = 17.5 Hz, J = 1.6 Hz), 5.29 (dd5 1H, H20b, J = llHz, J = 1.6 Hz), 5.51 ( d, 1H, H! 4, J=8.3Hz), 6.05 (dd, 1H, Η2 9, J=llHz, J=17.5Hz),; 7·〇(m,1H,aromatic H),7.18 (m , 2H, aromatic H), 7.3t, 1H, aromatic H5, J=8Hz). KB) 14-0-ΙΪ3-胍-styl-thiol V-acetamido- 1 truncated, hydrochloride a solution of 2.4 g of 14-0-[(3-amino-phenylthio)-ethinyl] truncated, 1.5 g of cyanamide and 0.44 ml of concentrated HC1 in 20 ml of dioxane. Stirring at room temperature for 28 hours "obtained 14-0-[(3-indolyl-phenylsulfanyl)-ethinyl] truncated as a hydrochloride salt crystal. The characterization data is referred to the above table.

實例I-D 14-0-[(3R*-幾基六氫吡啶-4-(R*)基）-硫基乙醯基]截短素與14-0-[(3S*-樂基六氫吡啶-4-(S*)基）-硫基-乙醯基】截短素，呈鹽酸鹽 形式（非對映異構混合物） 84364 • 70- 1331916 將已溶於1毫升2- 丁酮中之ΐ·06克截短側耳素·22·〇_甲苯磺 酸酯，慢慢添加至466毫克N-BOC-3-羥基-六氫吡啶斗硫醇與 224毫克第三-丁醇鉀在2〇毫升THF中之溶液内，將所得混合 物攪拌2小時，使所得混合物於鹽水與EiAc之間分配，以 0.1NHC1萃取，並分離所得液相。使所得有機相脫水乾燥， 並使所彳于之蒸發殘留物接受層析。將所得之14_〇_[(3r*_經基 7T氫吡啶-4-(R*)基）-硫基-乙醯基]截短素與14_〇_[(3S*_經基六氫 外匕淀-4-(S*)基）-硫基-乙酿基]截短素之混合物，以含鍵hci處j里EXAMPLE ID 14-0-[(3R*-Aminohexahydropyridin-4-(R*)))-thioethenyl] truncated and 14-0-[(3S*-yl hexahydropyridine) -4-(S*)yl)-thio-ethenyl] truncated, in the form of the hydrochloride (diastereomeric mixture) 84364 • 70- 1331916 will be dissolved in 1 ml of 2-butanone ΐ·06 g of pleuromutilin·22·〇_tosylate, slowly added to 466 mg of N-BOC-3-hydroxy-hexahydropyridine thiol and 224 mg of potassium third-butoxide at 2 The resulting mixture was stirred for 2 hours in THF (m.) THF. The mixture was partitioned between EtOAc and EtOAc. The resulting organic phase is dehydrated and dried, and the residue thus evaporated is subjected to chromatography. The obtained 14_〇_[(3r*_trans 7T-hydropyridin-4-(R*)))-thio-ethenyl] truncated hormone and 14_〇_[(3S*_经基六a mixture of hydrogen externally-precipitated 4-(S*)-based)-thio-ethyl-branched] truncations, containing the bond hci at j

’獲得其相應之鹽酸鹽。特徵鑒定數據參閱表5，實例42。 實例I-E 2,2,4_三氘-14-0-[((3-(S*)-羥基-六氫吡啶-4-(S*)-基）硫基）_乙醯基】 截短素，呈氣化氘形式' Obtain its corresponding hydrochloride salt. The characterization data is shown in Table 5, Example 42. Example IE 2,2,4_triter-14-0-[((3-(S*)-hydroxy-hexahydropyridin-4-(S*)-yl)thio)-ethinyl] truncated Prime, in the form of gasification

將實例ID中獲得之300毫克化合物在30毫升二氧陸圜與5毫 升DC1(20% ’在D2〇中）中之溶液，於250下保持6天。使溶-劑 自所得混合物中蒸發，並使濃縮殘留物接受冷滚乾燥。獲 得2,2,4-三氣-14-0-[((3-(S*)-幾基-六氫吡咬-4-(S*)-基）硫基）-乙醯基] 截短素’呈氣化氘形式。特徵鑒定數據參閱表5，實例41。 實例I_F l4-0-[3-(R*H(N-BOC-(R)-異纈草胺醯基•胺基-環己基）硫 基)-乙醯基】截短素⑻ 14_0-[3-(S*)-((N-B0C-(R)-異纈草胺醯基-胺基-環己小⑻卜基）硫基 )乙醯基]截短素（b) 14-0-[3-(S*)-((N-B0C-(R)-異纈草胺醯基-胺基-環己)硫基 )-乙醯基]截短素⑻ 84364 -71 - 1331916 14_0_[3_(r*H(N_boc讲異媒草胺醯基·胺基環己^料基)硫基 )_乙醯基】截短素⑼ 一 將已溶於U)毫升THF中之2.66克截短側耳素_22〇_甲苯磺酸 酯，慢慢添加至1.65克3-(N-B0C-(R)-異纈草胺醯基_胺基）環己 烷-(R/S)-硫醇與560毫克第三-丁醇鉀在25毫升ΤΗρ中之溶液内 ，將所得混合物攪拌2小時，並於鹽水與EtAc之間分配。以 0.1NHC1萃取所得混合物，使所得有機相脫水乾燥，蒸發溶 劑，並使所得之蒸發殘留物接受層析。獲得純 - ⑻14-0-[3-(R*H(N-B0C-(R)-異纈草胺醯基-胺基-環己基）硫 基）-乙醯基]截短素 (b) 14-0-[3-(S*)-((N-B0C-(R)-異纈草胺醯基-胺基_環己小們_基）硫 基）-乙醯基]截短素 (c) 14-0-[3-(S*)-((N-B0C-(R)-異纈草胺醯基-胺基 _環己]_(R*)基）硫 基）-乙酿基]截短素，及 - (d) 14-0-[3-(R*)-((N-B0C-(R)-異纈草胺醯基-胺基-環己小(s*)_基）硫 基）-乙醯基]截短素。1H-NMR(d6-DMSO): ⑻：6.5 (d，1H，NH，J=8.1Hz)，6.15, 5.1 (2xm，Η! 9，H2 〇，H2! )，5.52 (d，1H，J= 5·2Ηζ，4)，3.4 (m，1H，H〗！），3.55 (m，1H，CHN)，3.7 (m，. a-異纈草胺酿 基），3.2 (m，2H，H22)，2.7 (m，1H，SCH)，1.4 (s，9H，第三丁基），1.18, 1.45 (2xs, (CH3 5, (CH3 )j 8), 0.75, 0.88 (2xd, (CH3 )t 6, (CH3 7, J=5.4Hz). (b)： 6.15,5.1 (2xm,H19,H2〇,H20,5.52(0,1H, J=5.2Hz,^4), 3.4(m, 1H, H!! )，3.55 (m, 1H，CHN)，3.70 (m，a-異纈草胺醯基）,3.2 (m, 2H, H2 2 )， 2.7 (m，1H，SCH)，1_4 (s，9H，第三丁基），1.18, 1.45 (2xs，（CH3 h 5， (CH3), 8), 0.75, 0.88 (2xd, (CH3 )y 6, (CH3 ), 7, J=5.4Hz). 84364 -72· 1331916 (c) : 6.15,5.1 (2xm，H19，H2〇，H21)，5.52(d，lH，J=5.2Hz，H14)，3.4(m，1H， &amp; 】），13.9 (m，1H，CHN)，3.75 (m，a-異纈草胺醯基），3.2 (m，2H，H2 2)， 3.15 (m，1H，SCH)，1.4 (s，9H，第三丁基），U8,1.45 (2xs，（CHJ 5， (CH3 )i g), 0.75, 0.88 (2xd, (CH3 )j 6, (CH3 )j 7, J=5.4Hz). (d) ： 6.15,5.1 (2xm, Η2 9, H2〇,H2 0,5.52((1, 1H, J=5:2Hz, H! 4), 3.4 (m, 1H, % i )，3.9 (m，1H，CHN)，3_70 (m, a-異纈草胺醯基），3.2 (m，2H，H2 2), 3.15 (m，1H，SCH)，1.4 (s，9H，第三丁基），1.18, 1.45 (2xs，（CH3 h 5， (CH3), 8), 0.75, 0.88 (2xd, (CH3 ){6, (CH3 v, J=5.4Hz). ' 實例I-G _ 14-0-[3-(R*)-((R)-異纈草胺醯基-胺基-環己基)-硫基）-乙醯 基】截短素與14-0-[3-(S*)-((R)-異纈草胺醯基-胺基-環己-1-(S*)-基 )-硫基）-乙醯基】-截短素，呈鹽酸鹽形式（反式非對映異構物 之混合物） 使620毫克14-0-[3-(R*)-((N-B0C-(R)-異纈草胺醯基-胺基-環己'1-(R*)-基）硫基）-乙醯基]截短素與14-0-[3-(S*)-((N-B0C-(R)-異纈草胺 醯基-胺基-環己-1-(S*)-基）硫基）-乙醯基]截短素之1 : 1混合物 ，溶於10毫升無水含醚HC1與10毫升CH2C12之混合物中。將 混合物攪拌5小時，獲得及分離14-0[3-(R*)-((R&gt;異纈草胺醯基 -胺基-環己-1-(R*)-基）-硫基）-乙醯基]-截短素與14-0-[3-(S*H(R)-異 顯草胺醯基-胺基-環己基）〜硫基）-乙醯基]-截短素之反式 非對映異構混合物，呈鹽酸鹽形式。1H-NMR(d6-DMSO):旋 轉異構物·8·4(πι，1H，C=0NH)，8.15 (b，3H,NH3 + )，9, H2〇5H21), 5.52 (d, 1H, J=5.2Hz, H14),3.95 (m, 1H, CHNH3 + , 3.4 (m, 1H, Hu)，3.55(m，a -異纈草胺醯基）,3.2-3.3 (m，2H，H22 ),3.18 (m，lH, 84364 • 73- 1331916 SCH)，1 · 18, 1.45 (2xs，（CH3)! 5，（CH3 欠 8 )，0.9 (m，6H，CH(CH3 )2 )，0.75, 0.88 (2xd, (CH3 )x 6, (CH3), 7, J=5.4Hz)A solution of 300 mg of the compound obtained in the example ID in 30 ml of dioxanthine and 5 ml of DC1 (20% 'in D2?) was kept at 250 for 6 days. The solvent was evaporated from the resulting mixture, and the concentrated residue was subjected to cold-roll drying. Obtaining 2,2,4-trisole-14-0-[((3-(S*)-mono-hexahydropyridin-4-(S*)-yl)thio)-ethenyl] The short form is in the form of gasification. The characterization data is shown in Table 5, Example 41. EXAMPLE I_F l4-0-[3-(R*H(N-BOC-(R)-isoinvalidinylamino-cyclohexyl)thio)-ethenyl] truncated (8) 14_0-[ 3-(S*)-((N-B0C-(R)-isosporin-yl-amino-cyclohexan(8)-yl)thio)ethylidene] truncated (b) 14-0 -[3-(S*)-((N-B0C-(R)-isoinvalidinyl-amino-cyclohexyl)thio)-ethinyl] truncation (8) 84364 -71 - 1331916 14_0_ [3_(r*H(N_boc speaks isoamyl sulfhydryl-aminocyclohexyl) thio))ethinyl] truncated serotonin (9) a 2.66 gram fragment which has been dissolved in U) ml of THF Short-acting ear _22〇_tosylate, slowly added to 1.65 g of 3-(N-B0C-(R)-isochlorinyl-amino)cyclohexane-(R/S)-sulfur The alcohol was stirred with a solution of 560 mg of potassium 3-butoxide in 25 ml of EtOAc, and the mixture was stirred for 2 hr and partitioned between brine and EtAc. The resulting mixture was extracted with 0.1NHC1, and the obtained organic phase was dried and evaporated, evaporated, and evaporated. Obtaining pure -(8)14-0-[3-(R*H(N-B0C-(R)-isosastinal-yl-amino-cyclohexyl)thio)-ethinyl] truncated (b) 14-0-[3-(S*)-((N-B0C-(R)-isosalidominyl-amino-cyclohexanyl-yl)thio)-ethinyl] truncated (c) 14-0-[3-(S*)-((N-B0C-(R)-isosporinyl-amino-cyclohexyl]-(R*)yl)thio)-B Stimulating, truncated, and - (d) 14-0-[3-(R*)-((N-B0C-(R)-isoindicinyl-amino-cyclohexanide (s* ) _ yl) thio)-ethinyl] truncated. 1H-NMR (d6-DMSO): (8): 6.5 (d, 1H, NH, J = 8.1 Hz), 6.15, 5.1 (2xm, Η! 9, H2 〇, H2!), 5.52 (d, 1H, J= 5·2Ηζ,4),3.4 (m,1H,H〗!), 3.55 (m,1H,CHN),3.7 (m,. a-isochlorin), 3.2 (m, 2H, H22) , 2.7 (m, 1H, SCH), 1.4 (s, 9H, tert-butyl), 1.18, 1.45 (2xs, (CH3 5, (CH3)j 8), 0.75, 0.88 (2xd, (CH3)t 6 , (CH3 7, J=5.4Hz). (b): 6.15,5.1 (2xm, H19, H2〇, H20, 5.52 (0,1H, J=5.2Hz,^4), 3.4(m, 1H, H !! ), 3.55 (m, 1H, CHN), 3.70 (m, a-isosazone oxime), 3.2 (m, 2H, H2 2 ), 2.7 (m, 1H, SCH), 1_4 (s, 9H, tert-butyl), 1.18, 1.45 (2xs, (CH3 h 5, (CH3), 8), 0.75, 0.88 (2xd, (CH3)y 6, (CH3), 7, J=5.4Hz). 84364 -72· 1331916 (c) : 6.15,5.1 (2xm, H19, H2〇, H21), 5.52 (d, lH, J = 5.2 Hz, H14), 3.4 (m, 1H, &amp; 】), 13.9 ( m,1H,CHN), 3.75 (m, a-isosazone oxime), 3.2 (m, 2H, H2 2), 3.15 (m, 1H, SCH), 1.4 (s, 9H, tert-butyl ), U8, 1.45 (2xs, (CHJ 5, (CH3)ig), 0.75, 0.88 (2xd, (CH3)j 6, (C H3)j 7, J=5.4Hz). (d) : 6.15,5.1 (2xm, Η2 9, H2〇, H2 0, 5.52 ((1, 1H, J=5:2Hz, H! 4), 3.4 ( m, 1H, % i ), 3.9 (m, 1H, CHN), 3_70 (m, a-isochlorinyl), 3.2 (m, 2H, H2 2), 3.15 (m, 1H, SCH), 1.4 (s, 9H, tert-butyl), 1.18, 1.45 (2xs, (CH3 h 5, (CH3), 8), 0.75, 0.88 (2xd, (CH3){6, (CH3 v, J=5.4Hz ). 'Example IG _ 14-0-[3-(R*)-((R)-isosaurinyl-amino-cyclohexyl)-thio)-ethenyl] truncated and 14 -0-[3-(S*)-((R)-isochlorinyl-amino-cyclohexan-1-(S*)-yl)-thio)-ethinyl]-truncated , in the form of the hydrochloride salt (a mixture of trans diastereomers) to make 620 mg of 14-0-[3-(R*)-((N-B0C-(R)-isochlorinyl) -Amino-cyclohexyl 1 1-(R*)-yl)thio)-ethinyl] truncated and 14-0-[3-(S*)-((N-B0C-(R)- Isoflavamide-amino-cyclohexan-1-(S*)-yl)thio)-ethinyl] truncated 1:1 mixture dissolved in 10 ml of anhydrous ether containing HC1 and 10 ml In a mixture of CH2C12. The mixture was stirred for 5 hours to obtain and isolate 14-0[3-(R*)-((R&gt;isoindoline-amino-cyclohexan-1-(R*)-yl)-thio) -Ethyl]- truncated and 14-0-[3-(S*H(R)-isooxachlorinyl-amino-cyclohexyl)~thio)-ethenyl]-truncated A trans-diastereomeric mixture of the compounds in the form of the hydrochloride salt. 1H-NMR (d6-DMSO): rotamer·8·4 (πι, 1H, C=0NH), 8.15 (b, 3H, NH3 + ), 9, H2〇5H21), 5.52 (d, 1H, J = 5.2 Hz, H14), 3.95 (m, 1H, CHNH3 + , 3.4 (m, 1H, Hu), 3.55 (m, a - isoxachlorinyl), 3.2-3.3 (m, 2H, H22) , 3.18 (m, lH, 84364 • 73- 1331916 SCH), 1 · 18, 1.45 (2xs, (CH3)! 5, (CH3 ows 8), 0.9 (m, 6H, CH(CH3)2), 0.75, 0.88 (2xd, (CH3 )x 6, (CH3), 7, J=5.4Hz)

實例I-H 異纈草胺醢基-胺基-環己-1-(S*)-基）-硫基）-乙醢 基】-截短素與14-0-【3-(S*)-((R)-異纈草胺醯基-胺基-環己 基）-硫基）-乙醯基]-截短素，呈鹽酸鹽形式（順式非對映異構 物之混合物） 類似實例I-G之方法，但使用14-0-[3-(R*)-((N-B0C-(R)-異纈章 胺醯基-胺基-環己-1-(S*)-基）硫基）-乙醯基]截短素與14-0-[3-(S*)-((N-BOC-(R)-異纈草胺醯i -胺基-環己基）硫基）·乙醯基]截 短素之1 : 1混合物作為起始物質而獲得。iH-NMR(d6-DMSO) :旋轉異構物.8.52 (m，1H，C=ONH)，8.2 (b，3H，NH3 + )，6.15, 5.1 (2xm， Hi 9，H2〇，Η】i )，5.52 (d，1H，J-5.2Hz，Η! 4)，3.58 (m，1H，CHNH3 +，3.4 (m， 1H，i )，3_48 ㈣ a-異纈草胺醯基），3.2-3.3 (m，2H，H22)，2.75 (m，ίΗ， SCH), 1.18, 1.45 (2xs, (CH3 )j 5, (CH3 8 ), 0.9 (m, 6H, CH(CH3 )2 ), 0.75, 0.88 (2xd, (CH3 6, (CH3){7, J=5.4Hz)EXAMPLE IH Isoamylamine-Amino-cyclohexan-1-(S*)-yl)-thio)-ethinyl]-truncated and 14-0-[3-(S*)- ((R)-isosporin-yl-amino-cyclohexyl)-thio)-ethinyl]- truncated as a hydrochloride salt (a mixture of cis diastereomers) similar Example IG method, but using 14-0-[3-(R*)-((N-B0C-(R)-isoindolinyl-amino-cyclohexan-1-(S*)-yl) )thiol)-ethinyl] truncated and 14-0-[3-(S*)-((N-BOC-(R)-isochlorin 醯i-amino-cyclohexyl)thio ) · Ethyl] The 1 : 1 mixture of truncation is obtained as a starting material. iH-NMR (d6-DMSO): rotamer. 8.52 (m, 1H, C=ONH), 8.2 (b, 3H, NH3 + ), 6.15, 5.1 (2xm, Hi 9, H2 〇, Η) i ), 5.52 (d, 1H, J-5.2Hz, Η! 4), 3.58 (m, 1H, CHNH3 +, 3.4 (m, 1H, i ), 3_48 (iv) a-isochlorinated sulfhydryl), 3.2- 3.3 (m, 2H, H22), 2.75 (m, Η, SCH), 1.18, 1.45 (2xs, (CH3)j 5, (CH3 8 ), 0.9 (m, 6H, CH(CH3 )2 ), 0.75, 0.88 (2xd, (CH3 6, (CH3){7, J=5.4Hz)

實例I-I 14-0_[((N-(R)-異纈草胺醯基-一氮七圓烷_4_取8)_基硫基乙醯基 )]-截短素，呈鹽酸鹽形式 kI414-(R^):(2,4.6-三甲基-宇基-硫基）一氮七圚烷-酾 將828毫克3-(R/S)-(2,4,6-三甲基-字基-硫基）·環己酮_辟與57〇毫 克氯化甲苯磺醯在5毫升吡啶中之溶液，於室溫下攪拌4小 時，及於60。下再攪拌2小時。使所得混合物於稀硫酸(2毫升 濃Ηβ〇4，在15毫升％0中）與（^(¾之間分配，使所得有機 84364 -74· 1331916 相脫水乾燥，蒸發溶劑，並使蒸發殘留物接受層析。獲得4-(R/SH2,4,6-三曱基-苄基·硫基）-一氮七圜烷-2-_〇iH-NMR(d-6-DMSO): 7_5 (m，1H，NHCO)，6.8 (s，2H，芳族 H)，3.75 (s，2H，C6H5 CH2 S-)， 3_2 (m，1H，CHN)，3·1 (m，3H, CH2NH，CHS) AB-系統：νΑ=2.72, νΒ=2·65 (2H, CH2C=0, J=13.4Hz, J=4.5Hz) 2.13, 2.15, 2.3 (9H, 3xCH3) I-ffi) 4-(R/S)-(2,4,6-三甲基-字基-硫基）-一氮七圜掠， 將13.3克4-(R/S)-(2,4,6-三甲基-节基-硫基）—氮七圜燒-2-嗣添 加至15毫升1M LiAlH3溶液之混合物内，並添加50毫升THF。 將所得混合物於80°下加熱1小時，倒入200毫升20% NH4 C1水 溶液中，並以EtAc萃取所得混合物《使所得有機相脫水乾燥 ，並蒸發溶劑。獲得4-(R/S)-(2,4,6-三甲基-爷基-硫基）一氮七圜 烷。 I-IC) N-BOC-(4-(R/S)-(2,4,6-三曱基-宇基-硫基Y)—氣七圜虎 將2.63克4-(R/S)-(2,4,6-_H·甲基-爷基-硫基）一氮七圜燒、2.18—克 BOC-酐及1克三乙胺在1〇〇毫升THF中之溶液，於25。下攪拌12 小時，並使溶劑自所得混合物中蒸發。使所得之蒸發殘留 物於CH2 CL與1M HC1之間分配。使溶劑自所得之有機相中蒸 發，並使蒸發殘留物接受層析。獲得N-BOC-(4-(R/S)-(2,4,6-三甲 基爷基-硫基）)-一氮七圜燒。1H-NMR (d6-DMSO) : 6.8 (s，2H，芳族 H), 3.75 (s, 2H, C6H5cH2 S-), 3.2-3.5 (m, 4H, CH2NHCH2), 2.9 (m, 1H, CHS), 2.13,2.15,2.3 (9H, 3xCH3) I-IC)N-BOC-4-(R7S)-—氤七圜烷-硫醇 類似實例Π-D之方法，但使用適當起始物質獲得β I-ID) 14-0-「((N-B0C-—氮七圜烷-4-(R/SV某硫某Λ醢美截钼去 84364 •75- 1331916 將已溶於10毫升THF中之1·〇6克截短侧耳素·22_〇_甲苯磺酸 醋溶液’慢慢添加至420毫克N-BOC-(4-(R/S)—氮七圜烷-硫醇 與220毫克第二-丁醇钾在25毫升THF中之溶液内，並將所得 混合物攪拌2小時=使所得混合物於鹽水與EiAc之間分配， 將所得混合物以0.1NHC1萃取，使所得有機相脫水乾燥，蒸 發溶劑，並使所得之蒸發殘留物接受層析。獲得14_〇_[(^七〇(^ 一氮七圜乾-4-(R/S)-基）-硫基乙酿基)_截短素。1凡働汉(d6 _DMS〇): 6·15’5·1 (2xm，H19, H2〇，H2 0,5.52((1, 11^=5.2¾% 4 ),4.52 (d，1H，OH, J=6.2Hz) 3.4-(t, 1H, Ht!, J=6.2Hz), 3.1-3.4 (m, 6H, H2 2, CH2NCH2), 2.9 (m, 1H，SCH), 1.4(s，9H，第三了基），L18, 0.88 (2xd, (CH3)! 6, (CH3 )j 7, J=5.4Hz)Example II 14-0_[((N-(R)-isoindicinyl-a-nitrosentane_4_take 8)-ylthioethenyl)]- truncated, hydrochloride Form kI414-(R^): (2,4.6-trimethyl-ykyl-thio)-nitrosopenade-indole 828 mg 3-(R/S)-(2,4,6-trimethyl A solution of 57 gram of chlorinated toluene sulfonate in 5 ml of pyridine was stirred at room temperature for 4 hours and at 60. Stir for another 2 hours. The resulting mixture was partitioned between dilute sulfuric acid (2 ml of concentrated Ηβ〇4 in 15 ml%0) and (^(3⁄4), and the obtained organic 84364-74·1331916 phase was dehydrated and dried, the solvent was evaporated, and the residue was evaporated. Chromatography was carried out to obtain 4-(R/SH2,4,6-trimethyl-benzyl-thio)-nitros-7-nonane-7-〇iH-NMR (d-6-DMSO): 7_5 ( m,1H,NHCO), 6.8 (s,2H,aromatic H),3.75 (s,2H,C6H5 CH2 S-), 3_2 (m,1H,CHN),3·1 (m,3H, CH2NH,CHS AB-system: νΑ=2.72, νΒ=2·65 (2H, CH2C=0, J=13.4Hz, J=4.5Hz) 2.13, 2.15, 2.3 (9H, 3xCH3) I-ffi) 4-(R/ S)-(2,4,6-trimethyl-word-thio)-nitrogen hexamidine, 13.3 g of 4-(R/S)-(2,4,6-trimethyl-segment Addition to a mixture of 15 ml of 1 M LiAlH3 solution and addition of 50 ml of THF. The resulting mixture was heated at 80 ° for 1 hour and poured into 200 ml of 20% NH4 C1. In an aqueous solution, the resulting mixture was extracted with EtAc. The obtained organic phase was dried and dried, and evaporated to give 4-(R/S)-(2,4,6-trimethyl-yl-yl-thio)-nitrogen.圜. I-IC) N-BOC-(4-(R/S)-(2,4,6-three 曱-Yuji-thiol Y)-qiqixihu 2.63 g of 4-(R/S)-(2,4,6-_H.methyl-y-yl-thio)-nitrogen sulphate, 2.18-g A solution of BOC-anhydride and 1 g of triethylamine in 1 mL of THF was stirred at 25 °C for 12 h and solvent was evaporated from the mixture. The obtained residue was evaporated between CH2 CL and 1M HCl. The solvent is evaporated from the obtained organic phase, and the evaporation residue is subjected to chromatography to obtain N-BOC-(4-(R/S)-(2,4,6-trimethyl-yl-thio group). ))-N-nitrogen samarium. 1H-NMR (d6-DMSO): 6.8 (s, 2H, aromatic H), 3.75 (s, 2H, C6H5cH2 S-), 3.2-3.5 (m, 4H, CH2NHCH2) , 2.9 (m, 1H, CHS), 2.13, 2.15, 2.3 (9H, 3xCH3) I-IC) N-BOC-4-(R7S)--heptacane-thiol analogous example Π-D method, But use the appropriate starting material to obtain β I-ID) 14-0-"((N-B0C--a heptadecane-4-(R/SV sulphur some sulphur molybdenum to 84364 • 75- 1331916 will 1·〇6 g of pleuromutilin·22_〇_toluenesulfonic acid vinegar solution dissolved in 10 ml of THF was slowly added to 420 mg of N-BOC-(4-(R/S)-nitrogen a solution of an alkane-thiol with 220 mg of potassium second-butoxide in 25 ml of THF The mixture was stirred for 2 hours. The mixture was partitioned between brine and EtOAc. EtOAc (EtOAc) 14_〇_[(^七〇(^一氮七圜干-4-(R/S)-yl)-thioethyl)- truncation was obtained. 1凡働汉(d6 _DMS〇): 6·15'5·1 (2xm, H19, H2〇, H2 0, 5.52 ((1, 11^=5.23⁄4% 4 ), 4.52 (d,1H, OH, J=6.2Hz) 3.4-(t, 1H, Ht!, J=6.2Hz), 3.1-3.4 (m, 6H, H2 2, CH2NCH2), 2.9 (m, 1H, SCH), 1.4(s,9H, The third base), L18, 0.88 (2xd, (CH3)! 6, (CH3)j 7, J=5.4Hz)

Hg) M-〇-「(( 一氮垸-4-(R/S)-基）-硫某乙醯某η—游标辛，g _ 酸鹽形式 使400毫克14-0-[((N-B0C-—氮七圜烷-4-(R/S)-基）-硫基-乙醯‘基 )-截短素溶於10毫升無水含醚HC丨與1〇毫升CH2%之混合物中 。將所得混合物攪拌5小時，並分離14_〇_[((一氮七圜烷斗(R/s)_ 基）-硫基乙酿基）]-截短素，呈鹽酸鹽形式。特徵鑒定數據參 閱表1，實例14 » _ 14-Q-[((N·(拉』草胺醯基·一 f.七圜烷-4-Π^ν某v硫^^ Μ基）1-截短素，呈鹽龄眵彬嗥 將呈鹽酸鹽形式之245毫克14_〇_[((一氮七圜烷基硫 基乙酿基）]-截短素、110毫克BOC-R-纈胺酸、95毫克EDC及1〇〇 毫克三乙胺在10毫升THF中之混合物，於室溫下攪拌2小時 。使所得混合物於鹽水與EtAc之間分配，使所得有機相脫水 84364 -76- I331916 乾燥，蒸發溶劑，並使所得之蒸發殘留物接受層析。獲得 14-0_[(帅0(：讲異纈草胺醯基一氮七圜烷_4_购-基）硫基乙 醯基）]-截短素-鹽酸鹽。經由以5毫升含謎HC1處理，使 保護基分裂，獲得14-〇-[((N，(R)_異纈草胺醯基一氮七圜烷4 (R/S)-基）-硫基乙醯基）]_截短素，呈鹽酸鹽形式。特徵鑒定數 據參閱表1，實例15 »Hg) M-〇-"((a 垸-4-(R/S)-yl)- sulphur 醯 醯 游 游 游 游 游 游 , , , g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g -B0C--a heptadecane-4-(R/S)-yl)-thio-ethionyl- tracholone is dissolved in a mixture of 10 ml of anhydrous ether-containing HC丨 and 1 mL of CH2% The resulting mixture was stirred for 5 hours, and 14_〇_[((aza-heptaindole(R/s)-yl)-thioethenyl)]- truncated as a hydrochloride salt was isolated. For the characterization data, see Table 1, Example 14 » _ 14-Q-[((N·(拉上草胺醯基·一 f.七圜烷-4-Π^ν某v硫^^ Μ) 1- Truncated, 249 mg of 14-〇_[((N-sodium decylalkylthio)]- truncated, 110 mg BOC-R- in the form of the hydrochloride salt A mixture of lysine, 95 mg of EDC and 1 mg of triethylamine in 10 ml of THF was stirred at room temperature for 2 hr. The mixture was partitioned between brine and EtAc to dehydrate the obtained organic phase 84364-76 - I331916, drying, evaporating the solvent, and subjecting the obtained evaporation residue to chromatography. Obtained 14-0_[(帅0(: 缬 缬 醯 醯 一 一 一 圜 _ _ _)醯Base)]- truncation-hydrochloride. The protective group was cleaved by treatment with 5 ml of mystery HC1 to obtain 14-〇-[((N,(R)_isosachlorinyl-nitrogen-7圜) Alkane 4 (R/S)-yl)-thioethenyl)]- truncation, in the form of the hydrochloride. For characterization data, see Table 1, Example 15 »

實例I-J 14_〇-[((一氮七園烷-2-酮-4-(R/S)·基）_硫基乙醯基）】_截短素 類似只例IAB)之方法，自4-(R/S)-酿基一氮七圜烷《 -2-_開始 而獲得。特徵鑒定數據參閱表5，實例43。EXAMPLE IJ 14_〇-[((N-N-octadecane-2-one-4-(R/S))))-thioethenyl)]-Termin is similar to the method of only Example IAB), since 4-(R/S)-bristing-nitrogen heptane was obtained at the beginning of -2-_. The characterization data is shown in Table 5, Example 43.

實例I-K 14-0-{[(3-萌基-環戊-(R/S)-基)·硫基】_乙酿基}_截短素 將3.95克14-巯基-乙酿基-截短素在5毫升!7比咬中之溶液，以 0.81克環戊-2-烯酮與催化量之三乙胺處理。將所得混合物.於 室溫下揽拌3小時’以EtAc稀釋，並以IN HC1與Η2 Ο萃取。 使所得有機相脫水乾燥，蒸發溶劑，並使所得之蒸發殘留 物接受層析。獲得14-0-{[(3-酮基-環戊-(R/S)-基）-硫基乙醯基} 截短素。特徵鑒定數據參閱表5，實例44。Example IK 14-0-{[(3-Mercapto-cyclopentyl-(R/S)-yl)·thio]_Ethyl}}- truncated 3.95 g of 14-mercapto-ethyl-based The short solution was treated with 0.81 g of cyclopent-2-enone and a catalytic amount of triethylamine in a 5 ml! 7 bit solution. The resulting mixture was stirred at room temperature for 3 hours to be diluted with EtAc and extracted with IN HCl and EtOAc. The obtained organic phase was dried to dryness, the solvent was evaporated, and the obtained evaporation residue was subjected to chromatography. 14-0-{[(3-Ketyl-cyclopentyl-(R/S)-yl)-thioethenyl} truncation was obtained. The characterization data is shown in Table 5, Example 44.

實例I-L 14-0-{[(3-羥亞胺基-環戊-(R/S)-基）·硫基】-乙贐基卜截短素（同側 與對側形式） 將3_88克14-0-{[(3-酮基-環戊-(R/S)-基）-硫基]-乙醯基卜截短素 與566毫克羥胺鹽酸鹽及1_13毫升三乙胺在40毫升DMF中授 拌過夜。自所得混合物中蒸餾出溶劑’使所得之蒸掏殘留 84364 -77- 1331916 物溶於EtAc中’並將所得混合物以〇 1NHC1與鹽水萃取。使 所得有機相脫水乾燥，並蒸發溶劑。獲得14_〇_{[(3_羥亞胺基_ 環戊-(R7S)-基）-硫基]•乙醯基卜截短素呈同側與呈對側形式 (混合扬’使混合物無論是藉層析分離以獲得純同側與純 對側形式，或以所得混合物之形式使用於進一步反應步輝 中。特徵鑒定數據參閱表3，實例24。 實例Ι_Μ 14-〇-{[(3-(2-二乙胺基-乙氧基亞胺基)_環戊-⑻印基）_硫基]_乙磕 基}-截短素，呈鹽酸鹽形式 將200毫克14-〇-{[(3_羥亞胺基-環戊-(R/S)_基）_硫基]_乙醯基卜 截短素與70毫克氯化二乙胺基乙烷鹽酸鹽在5毫升CH2 Cl2中 攪拌’添加90毫克第三-丁醇鉀，並於室溫下持續攪拌2天 。使溶劑自所得混合物中蒸發，使蒸發殘留物接受層析， 將所得之有關聯層析溶離份，於Et20與0.1NHC1之間分配：， 並使水層凍乾。獲得14-〇-{[(3-(2-二乙胺基-乙氧基亞胺基環 戊-(R/S)-基）硫基]-乙醯基}_截短素鹽酸鹽（同側/對側混合物） 。特徵鑒定數據參閱表3，實例26。Example IL 14-0-{[(3-hydroxyimino-cyclopentyl-(R/S)-yl)-thio]-ethenyl truncation (ipsilateral and contralateral) 3_88 g 14-0-{[(3-keto-cyclopentyl-(R/S)-yl)-thio]-ethenyl truncation with 566 mg of hydroxylamine hydrochloride and 1-13 ml of triethylamine at 40 Mix overnight in ML DMF. The solvent was distilled off from the obtained mixture to make the obtained distilled residue 84364 - 77 - 1331916 dissolved in EtAc, and the mixture was extracted with 〇 1NHC1 and brine. The resulting organic phase was dried by dehydration and the solvent was evaporated. Obtaining 14_〇_{[(3_hydroxyimino)-cyclopentyl-(R7S)-yl)-thio]-acetamidole truncated flavonoids in ipsilateral and contralateral forms Whether it is by chromatographic separation to obtain pure ipsilateral and pure contralateral forms, or in the form of the resulting mixture for further reaction step glory. For characterization data, see Table 3, Example 24. Example Ι _ Μ 14-〇-{[( 3-(2-diethylamino-ethoxyimino)-cyclopentyl-(8)indolyl)-thio]-ethenyl}- truncated, 200 mg 14-〇 as the hydrochloride salt -{[(3_hydroxyimino-cyclopentyl-(R/S)-yl)-thio]-ethenyl truncated with 70 mg of diethylaminoethane hydrochloride in 5 Stir in 90 ml of CH2Cl2, add 90 mg of potassium tributoxide, and continue stirring at room temperature for 2 days. Evaporate the solvent from the resulting mixture, subject the evaporation residue to chromatography, and dissolve the resulting chromatographic separation. Partition, partition between Et20 and 0.1NHC1: and freeze the aqueous layer to obtain 14-〇-{[(3-(2-diethylamino)-ethoxyiminocyclopentane-(R/S )-yl)thio]-ethenyl}- truncated hydrochloride (Ipsilateral/contralateral mixture). Characterization data Reading Table 3, Example 26.

實例I-N 14-0-[(2-(R*)-((R)-異纈草胺醯基)-胺基-環己基）_硫基乙醯 基)】_截短素鹽酸鹽 逆A) 14-〇-「((2-CR*V胺基環己-1-(R*V基）-硫基乙醯基ΥΙϋ辛 將已溶於5毫升THF中之1.06克截短側耳素-22-0-甲苯磺酸酯 ，慢慢添加至334毫克呈鹽酸鹽形式之2-(R*)-胺基環己硫 醇（參閱，例如 G.Kavadias 與 R.Droghini，Can· J. Chem. 1978, 56, 2743) 84364 -78- 1331916 與92毫克鈉在50毫升EtOH中之溶液内，將所得混合物揽掉2 小時，於鹽水與EtAc之間分配，以O.in HC1萃取，及乾燥。 使溶劑自所得混合物中蒸發，並使蒸發殘留物接受層析。 獲得14-0-[((2-(R*)-胺基環己基）-硫基乙醯基）]_截短素。 1H-NMR(d6-DMSO)： 6.15,5.1 (2xm, Hi 9, H20, H2 j), 5.52 (d, 1H, J=5.2Hzs Hi 4), 2.45 (m, 1H, CHNH), 3.21 (s2H, H2 2), 3.4 (d, 1H, Hj}, J=5Hz), 2.55 (m 1H，CHS)，1.18, 1.45 (2xs，（CH3 )丨 5，（CH3 )丨 8 )，0.9 (m, 6H, CH(CH3 )2 )，0.75, 0.88 (2xd, (CH3 )i 6, (CH3 7, J=5.4Hz). - I-NB) 14-0-[^2-(R*V(XR·)-異賴草胺醯基）-胺某·環己小某硫甚 乙酿基）1-截短素，呈鹽酸鹽形式 將245毫克14-0-[((2-(R*)-胺基環己基）_硫基乙酿基）]截 短素、110觉克BOC-(R)-顯胺酸、95毫克EDC及68毫克HOBT在 10當升THF中之混合物’於室溫下揽摔2小時。使所得混合 物於鹽水與EtAc之間分配’使所得有機相脫水乾燥，蒸發-溶 劑’並使蒸發殘留物接受層析。獲得14-〇-[((2-(R*)-(n_boc·⑻· 異纈草胺醯基）-胺基-環己-1-(R*)-基）-硫基乙醯基）]·截短素。經 由以5毫升含醚HC1處理，使BOC-保護基分裂，獲得i4-〇-[(2-(R*)-((R)-異網草胺酿基）-胺基-環己-1_(r*)_基）-硫基乙醯基）]_截 短素，呈鹽酸鹽形式。1H-NMR(d6-DMSO):非對映異構物）：8_45 (m, 1H, NHC=0), 8.1 (b, 3H, NH3 + ), 6.15,5.1 (2xm, Hi 9, H2〇, H2 !), 5.52 (d3 1H, J=5.2Hz，Hi 4 )，3.55 (m，1H，a-H-異願草胺醯基），3.6Ο (m, ih，CHNH)， 3.26-3.35 (τη，2H，H2 2)，3.4 (m，1H，&amp; i), 4.5 (d，1H，OH，J=6.2Hz)，2.6, 2.75 (2xm，1H，CHS)，1.25(b，3H，CH3CS)，1.18, 1.45(2xs，（CH3)15，（CH3)18)， 0.9 (m, 6H, CH(CH3 )2), 0.75, 0.88 (2xd, (CH3 )2 6, (CH3 )λ 7, J=5.4Hz) 84364 -79- 1331916 實例ι-ο 14-0-{[(3S，3aS，6S，6aR)-6-胺基-六氫-呋喃并[3,2-b】呋喃-3-基硫基卜 乙醯基}-截短素鹽酸鹽 I-OA)甲苯 _4-磺酸（3R，3aS,6R，6aRV6-羥基-六氫-咕喃 # p，2_b^ 成 _ 3-基酯 將 5 克（3R，3aS，6R，6aR)-：r^ 氫-吱喃并[3,2-b]吱喃-3,6-二醇在 5〇 毫 升吡啶中之溶液，與7.8克氯化甲苯磺醯一起攪拌16小時。 自所得混合物中蒸餾出溶劑，並使所得之蒸餾殘留物溶於 EtAc中，且以1NHC1、飽和NaHC〇3水溶液及氐0萃取。使所 得有機層脫水乾燥’蒸發溶劑’並使蒸發殘留物接受層析 。獲得曱苯斗磺酸⑼邮版加❼各羥基-六氫-吱喃并阳叫呋 喃-3-基酯。iHNMR(DMSO-d6): 7.8(d，2H，Ar-H，J=8.6Hz)，7.5(d，2H， Ar-H，J=8.6Hz)，4.8-4.9 (m, 2H，H-3, 6-OH)，4.4 (dd，1H，H-3a，J=4.7 與5·0Ηζ)， 4.2 (dd，1H，H_6a，J=4.7 與 4·8Ηζ)，3.9-4.0 (m，1H，H-6), 3.7-18 (m，2H，H-2 與 H-5)，3.6 (d，1H，H-2, J=9.3 與 7.1Hz)，3.23.4 (m，1H，H-5)，2.4 (s，3H，Ar- CH3). !^&gt;B)_(3R，3aR，6S，6aRV6-疊氮基-六氫-咕喃并丨3 2伸麥n碑 將2.5克曱苯-4-磺酸（311^，队加尺)-6-羥基-六氫-呋喃并[3j2_b] 咬喃-3-基g旨在30毫升DMF中之溶液，與0.8克疊氮化鈉，於 回流下，一起加熱2小時，蒸餾出溶劑，並使蒸餾所得之殘 留物溶於EtAc中，且以40萃取。使所得有機相脫水乾燥’ 並蒸發溶劑。獲得（3R，3aR，6S，6aR)-6-疊氮基-六氫_吱喃并[3j2七] 吱喃-3-醇。 Ι.-ΏΡ).{(城3&amp;匕^6说)-6-羥基-六氫-吱喃并「3 2仲参4 J·芊卜畔甲 •80· 84364 1331916 基酸第三-丁酯 於1.5克（311，3311，63,6311)-6-疊氮基_六氫_呋喃并[3,2七]呋喃_3_醇 在25¾:升二氧陸圜中之溶液内，添加乃毫克鈀/炭)， 並使所得混合物接受氫化作用。將所得混合物過濾，並與3 2 毫升乙基二異丙基胺及4.1克（BOC)2 〇攪拌過夜。使溶劑自所 得混合物中蒸發。使所得之蒸發殘留物溶於EtAc中，並以飽 和鈉NaHC〇3水溶液、IN HC1及鹽水萃取。使所得有機相脫水 乾燥，蒸發溶劑，並使所得之蒸發殘留物接受層析。獲桴 {(3S，3aR，6R76aR)-6-：^ 基-7T 氫-ρ夫喃并[3,2-b]吱喃-3-基}_胺曱基酸 第二-丁酯。1H NMR (DMSO-d6 ) : 7.1 (bs，1HNH), 4.8 (d, 1H，6-OH，J= 10Hz)’ 4.3 (dd，lH，H-6a，J=4.6 與 4·3Ηζ)，4.27 (d，1H，H-3a，J=4.3Hz), 4.0-4.1 (m, 1H, H-6), 3.2-3.85 (m，5H，2xH-2, H-3, 2xH-5), 1.4 (s，9H,第三 丁基） I_-pD)甲苯-4二續酸（3R，3aS,6S,6aRV6-第三-丁氫羰某胺甚_ 士舒吐 喃并「3,2-b&gt;決喃-3-基酯 將700愛克{(3S，3aR，6Rj6aR)-6-起基-六氫-咬喃并夫喃-3-基} 胺甲基酸第三-丁酯在10毫升吡啶中之溶液與785毫克氯化甲 苯磺醯’一起攪拌16小時，蒸餾出溶劑，並使蒸餾殘留物 溶於EtAc中，且以1NHC1、飽和NaHC〇3水溶液及h2〇萃取。 使所得有機層脫水乾燥’並蒸發溶劑。獲得甲苯_4_續酸 (3R，3aS，6S，6aR)-6-第三-丁氧羰基胺基-六氫-呋喃并[3,2七]吱喃！ 基酉旨。 I-〇E) 14-0-{[(3S^3aS，6S，6aRV6-第三-丁氣基碳胺基-六氣-吟喃许 [3之七]呋喃-3-基硫基V乙醯某μ裁短素 將267毫克第三-丁醇钾添加至950毫克甲苯|續酸 84364 -81 - 1331916 (3R，3aS，6S，6aR)-6-第三-丁氧羰基胺基-六氫_吱喃并[3,2七]呋喃_3_ 基酯與1032耄克14-魏基-乙酿基·截短素在2〇毫升dmSO中之溶 液内。將所得混合物於70。下攪拌丨小時，並於EtAc&amp;鹽水之 間分配。將所得有機相以％0洗滌，脫水乾燥，並蒸發溶劑 。使所得之蒸發殘留物接受層析。獲得14_〇_{[(3s，3aS，6s，6aR)_6· 第二-丁氧羰基-胺基-六氫-呋喃并[3,2-b]呋喃-3-基硫基]-乙醯基 }-截釦素。1HNMR(DMSO-d6): 7.1 (bs，1HNH)，6.1，5.05,5.0^01,^9， ο &gt; H2 j), 5.55 (d, 1H, H! 4, J=8.2Hz), 4.5 (m, 2H, Hj t -OH, H-3a'), 4.4 (d,&quot; 1H, H-6a', J=4Hz), 3.3-4.0 (m, 9H, H-2', H-31, H-5', H-61, H,!, H2 2 )5 1.36 (s, 9H，第三-丁基)，1.34, 1.05 (2xs，（CH3)! 5，（CH3 )】8 )，0.8, 0.62 (2xd，（CH3)! 6， (CH3)17, J=6.8Hz). I-OF) 14-〇-{[QS，3aS，6S，6aR)-6-胺基-六氤-咬喃 #「3,2_bl咕喃冬某硫 基1-乙酿基丨-截短素 使950毫.克14-0-{[(33,333邳加11)-6-第三-丁氧羰基胺基_六氫二吱 哺并[3,2-b]吱喃-3-基硫基]•乙醯基}-截短素溶於2〇毫升CH2 Cl2 中’並將所得混合物與3毫升TFA —起撥拌2小時。將所得混 合物以EtAc稀釋，並以飽和NaHC03水溶液萃取。使所得有機 相脫水乾燥’並蒸發溶劑。獲得14-〇-{[(3S，3aS，6S，6aR)-6-胺基-風-咬喃并[3,2-b]咬喃-3-基硫基]-乙酿基}-截短素。 胺基-六氫-咕喃并「3.2-bl咭喃-3-基硫 基1-乙醯基丨截短素，呈镑酸鹽形式 使 180 毫克 i4-0-{[(3S，3aS，6S,6aR)-6-胺基-六氫-吃喃并[3,2-b]吱喃 -3-基硫基]-乙醯基}•截短素於乙醚與〇.1N HC1之間分配。使所 得之水層凍乾。獲得14-〇-{[(3S，3aS,6S，6aR)-6-胺基-六氫-呋喃并 84364 -82- 1331916 [3,2-b]吱喃-3-基硫基]-乙醯基截短素，呈鹽酸鹽形式。特徵 鑒定數據參閱上文表4，實例36a ^ —Example IN 14-0-[(2-(R*)-((R)-isoindolyl)-amino-cyclohexyl)-thioethenyl)]-Termin hydrochloride A) 14-〇-"((2-CR*V Aminocyclohex-1-(R*V))-thioethenyl octyl octanoate 1.06 g of pleuromutilin dissolved in 5 ml of THF -22-0-tosylate, slowly added to 334 mg of 2-(R*)-aminocyclohexyl mercaptan as the hydrochloride salt (see, for example, G. Kavadias and R. Droghini, Can J Chem. 1978, 56, 2743) 84364 -78- 1331916 and the solution of 92 mg of sodium in 50 ml of EtOH, the mixture was taken off for 2 hours, partitioned between brine and EtAc, extracted with O.in HC1. And drying. The solvent is evaporated from the obtained mixture, and the evaporation residue is subjected to chromatography to obtain 14-0-[((2-(R*)-aminocyclohexyl)-thioethenyl)]_ 1H-NMR (d6-DMSO): 6.15,5.1 (2xm, Hi 9, H20, H2 j), 5.52 (d, 1H, J=5.2Hzs Hi 4), 2.45 (m, 1H, CHNH), 3.21 (s2H, H2 2), 3.4 (d, 1H, Hj}, J=5Hz), 2.55 (m 1H, CHS), 1.18, 1.45 (2xs, (CH3 )丨5, (CH3 )丨8 ), 0.9 (m, 6H, CH(CH3 )2 ), 0.75, 0.88 (2xd, (CH3 )i 6, (CH3 7, J=5.4Hz). - I-NB) 14-0-[^2-(R*V(XR·)-isolysamine sulfhydryl)-amine 环·cyclohexan thiophene) - truncation, in the form of the hydrochloride salt, 245 mg of 14-0-[((2-(R*)-aminocyclohexyl)-thioethyl)] truncation, 110 gram BOC-( R)- leucine, 95 mg EDC and a mixture of 68 mg HOBT in 10 liters of THF were shaken at room temperature for 2 hours. The resulting mixture was partitioned between brine and EtAc. Evaporation-solvent' and subjecting the evaporation residue to chromatography to give 14-[rho]-[((2-(R*)-(n-boc·(8)·isosachlorinyl)-amino-cyclohexan-1-( R*)-yl)-thioethenyl)] truncation. The BOC-protecting group was cleaved by treatment with 5 ml of ether-containing HC1 to obtain i4-〇-[(2-(R*)-( (R)-Isoamyl sulphate)-Amino-cyclohexan-1_(r*)-yl)-thioethenyl)]- truncation, in the form of the hydrochloride salt. 1H-NMR (d6-DMSO): diastereomer): 8_45 (m, 1H, NHC=0), 8.1 (b, 3H, NH3 + ), 6.15, 5.1 (2xm, Hi 9, H2〇, H2 !), 5.52 (d3 1H, J=5.2Hz, Hi 4 ), 3.55 (m, 1H, aH-isoachlorin), 3.6Ο (m, ih, CHNH), 3.26-3.35 (τη, 2H, H2 2), 3.4 (m, 1H, &amp; i), 4.5 (d, 1H, OH, J = 6.2 Hz), 2.6, 2.75 (2xm, 1H, CHS), 1.25 (b, 3H, CH3CS) , 1.18, 1.45 (2xs, (CH3)15, (CH3)18), 0.9 (m, 6H, CH(CH3)2), 0.75, 0.88 (2xd, (CH3)2 6, (CH3)λ 7, J =5.4Hz) 84364 -79- 1331916 Example ι-ο 14-0-{[(3S,3aS,6S,6aR)-6-Amino-hexahydro-furo[3,2-b]furan-3- Thiothiophene}- truncated hydrochloride I-OA) toluene_4-sulfonic acid (3R,3aS,6R,6aRV6-hydroxy-hexahydro-purine#p,2_b^ into -3- a solution of 5 g (3R, 3aS, 6R, 6aR)-:r^hydro-indolo[3,2-b]pyran-3,6-diol in 5 ml of pyridine, and 7.8 The chlorotoluene sulfonium chloride was stirred for 16 hours. The solvent was distilled off from the obtained mixture, and the obtained distillation residue was dissolved in EtAc, and 1N HCl, saturated aqueous solution of NaHC? The obtained organic layer was dehydrated and dried to evaporate the solvent and the evaporation residue was subjected to chromatography to obtain the hydrazine sulfonic acid (9). The hydroxy-hexahydro-hydrazino and yanofuran-3-yl ester were added. iHNMR (DMSO-d6): 7.8 (d, 2H, Ar-H, J = 8.6 Hz), 7.5 (d, 2H, Ar-H, J = 8.6 Hz), 4.8-4.9 (m, 2H, H-3) , 6-OH), 4.4 (dd, 1H, H-3a, J=4.7 and 5·0Ηζ), 4.2 (dd, 1H, H_6a, J=4.7 and 4. 8Ηζ), 3.9-4.0 (m, 1H, H-6), 3.7-18 (m, 2H, H-2 and H-5), 3.6 (d, 1H, H-2, J=9.3 and 7.1 Hz), 3.23.4 (m, 1H, H-) 5), 2.4 (s, 3H, Ar- CH3). !^&gt;B)_(3R,3aR,6S,6aRV6-azido-hexahydro-purine 丨3 2 Anthraquinone-4-sulfonic acid (311^, team plus ruler)-6-hydroxy-hexahydro-furo[3j2_b] N--3-yl g is aimed at a solution of 30 ml of DMF, with 0.8 g of azide The sodium was heated under reflux for 2 hours, the solvent was distilled off, and the residue obtained by distillation was dissolved in EtAc and extracted at 40. The resulting organic phase was dried to dry&apos; and the solvent was evaporated. (3R, 3aR, 6S, 6aR)-6-azido-hexahydro-indolo[3j2-7]nonan-3-ol was obtained. Ι.-ΏΡ).{(城3&匕^6说)-6-Hydroxy-hexahydro-purine and "3 2 secondary ginseng 4 J·芊卜畔甲•80· 84364 1331916 carboxylic acid third-butyl ester 1.5 g (311, 3311, 63, 6311)-6-azido-hexahydro-furo[3,2-7]furan-3-ol in a solution of 253⁄4: liter of dioxane, added in milligrams Palladium on charcoal, and the resulting mixture was subjected to hydrogenation. The mixture was filtered and stirred with 3 2 mL of ethyldiisopropylamine and &lt;RTI ID=0.0&gt;&gt; The obtained evaporation residue was dissolved in EtAc, and extracted with saturated aqueous NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 3S,3aR,6R76aR)-6-:^ -7-T-hydro-pf-pyrano[3,2-b]pyran-3-yl}-amino-carbamic acid second-butyl ester. 1H NMR (DMSO- D6) : 7.1 (bs,1HNH), 4.8 (d, 1H,6-OH, J= 10Hz)' 4.3 (dd,lH,H-6a,J=4.6 and 4·3Ηζ), 4.27 (d,1H, H-3a, J=4.3Hz), 4.0-4.1 (m, 1H, H-6), 3.2-3.85 (m, 5H, 2xH-2, H-3, 2xH-5), 1.4 (s, 9H, Third butyl) I_-pD) toluene-4 sucrose acid (3R, 3aS, 6S, 6aRV6-tris-butanhydrocarbylamine) 士士舒吐 and "3,2-b&gt; cumyl-3-yl ester will be 700 Aike {(3S,3aR,6Rj6aR)-6-starting-hexahydro-bromo-fusan-3-yl} A solution of a third methyl butyl acid in 10 ml of pyridine with 785 mg of chlorinated The toluene sulfonate was stirred for 16 hours, the solvent was distilled off, and the distillation residue was dissolved in EtAc and extracted with 1N EtOAc, sat. NaH.sub.3 aqueous solution and H.sub.2. The obtained organic layer was dehydrated and evaporated to yield toluene. _4_Continuous acid (3R,3aS,6S,6aR)-6-tris-butoxycarbonylamino-hexahydro-furo[3,2-7] oxime! 基酉. I-〇E) 14 -0-{[(3S^3aS,6S,6aRV6-Third-butane-based carbonamine-six-gas-吟 许 [ [7] uran-3-ylthio V 醯 μ μ μ cut Add 267 mg of potassium third-butoxide to 950 mg of toluene|continued acid 84364-81 - 1331916 (3R, 3aS, 6S, 6aR)-6-tris-butoxycarbonylamino-hexahydro-pyrano[ 3,2-7] furan-3-yl ester and 1032 g of 14-Williyl-ethyl-branched truncation in a solution of 2 ml of dmSO. The resulting mixture was at 70. Stir for a few hours and distribute between EtAc &amp; brine. The resulting organic phase was washed with %0, dried over water and evaporated. The resulting evaporation residue was subjected to chromatography. Obtain 14_〇_{[(3s,3aS,6s,6aR)_6· 2nd-butoxycarbonyl-amino-hexahydro-furo[3,2-b]furan-3-ylthio]-B醯基}-Cut factor. 1H NMR (DMSO-d6): 7.1 (bs, 1HNH), 6.1, 5.05, 5.0^01, ^9, ο &gt; H2 j), 5.55 (d, 1H, H! 4, J = 8.2 Hz), 4.5 ( m, 2H, Hj t -OH, H-3a'), 4.4 (d, &quot; 1H, H-6a', J=4Hz), 3.3-4.0 (m, 9H, H-2', H-31, H-5', H-61, H,!, H2 2 )5 1.36 (s, 9H, third-butyl), 1.34, 1.05 (2xs, (CH3)! 5, (CH3)] 8 ), 0.8 , 0.62 (2xd, (CH3)! 6, (CH3)17, J=6.8Hz). I-OF) 14-〇-{[QS,3aS,6S,6aR)-6-Amino-Six-Bite-Bite喃# "3,2_bl咕 冬 某 thiol 1-ethyl aryl hydrazine - truncation 950mg. gram 14-0-{[(33,333邳11)-6-T-butoxycarbonylamino _Hexahydroquinone-feeding [3,2-b]pyran-3-ylthio]•ethenyl}- truncation in 2 ml of CH2Cl2' and the resulting mixture with 3 ml of TFA The mixture was stirred for 2 hours. The mixture was diluted with Et.sub.2 and extracted with saturated aqueous NaHCOs. Amino-wind-bite-and-[3,2-b]-anthracen-3-ylthio]-ethlyl}- truncated. Amino-hexahydro-purine and "3.2-bl" 3-ylthio-1-ethylindenyl quinone Form 180 mg i4-0-{[(3S,3aS,6S,6aR)-6-amino-hexahydro-aceto[3,2-b]pyran-3-ylthio]-acetamidine The cleavage element is partitioned between diethyl ether and hydrazine. 1N HCl. The resulting aqueous layer is lyophilized to obtain 14-〇-{[(3S,3aS,6S,6aR)-6-amino-hexahydro- Furan and 84364-82- 1331916 [3,2-b]pyran-3-ylthio]-ethenyl truncated as a hydrochloride salt. For characterization data, see Table 4 above, Example 36a ^ —

實例I-P 14-0-{[(3S，3aS，6S，6aR)-6-((R)·胺基-3-甲基-丁醯基胺基)_六氫 _咬喃 并丨3,2-b】呋喃·3-基硫基】-乙醯基μ截短素，呈鹽酸鹽形式 將400窀克14-〇-{[(33加，63加11)-6-胺基-六氫_呋喃并[3}2七]呋喃 -3-基硫基]-乙醯基）}截短素在2〇毫升Ch2C12中之溶液，以128 毫克n-b〇c-(r)-顯胺酸、毫克EDC、104毫克H〇BT處理，並 將所得混合物於室溫下攪拌過夜。將所得混合物以CH2C12稀 釋，以％〇萃取，脫水乾燥，及蒸發溶劑。使所得之蒸發殘 留物於矽膠上接受層析，將所得之有關聯層析溶離份以 CH2 (¾中之TFA再處理一次，蒸發溶劑，使所得之蒸發殘留 物於恥〇與〇.1NHCl之間分配，並使所得之水層凍乾。獲得 【^^-{[(城祕风石说^⑻-之-胺基各甲基-丁醯基胺基卜六氫：咳 喃并[3,2-b]呋喃-3-基硫基]-乙醯基卜截短素，呈形式鹽酸鹽。 特徵鑒定數據參閱表5 ,實例38a »Example IP 14-0-{[(3S,3aS,6S,6aR)-6-((R)·Amino-3-methyl-butanylamino)-hexahydro- 咬 丨 丨 3,2-b 】 furan 3-ylthio]-ethenyl μ truncation, in the form of the hydrochloride salt 400 g 14-〇-{[(33 plus, 63 plus 11)-6-amino-hexahydro_ a solution of furo[3}2h-7-furan-3-ylthio]-ethenyl)} truncation in 2 ml of Ch2C12 with 128 mg of nb〇c-(r)-leucine, mg EDC, 104 mg of H〇BT was worked up and the mixture was stirred at room temperature overnight. The resulting mixture was diluted with CH2C12, extracted with EtOAc, dried over water and evaporated. The resulting evaporation residue was subjected to chromatography on silica gel, and the resulting chromatographic fractions were treated with CH2 (TTA in 3⁄4), and the solvent was evaporated to give the residue as evaporating residue in s. Distribute and let the obtained water layer freeze-dried. Obtain [^^-{[(城秘风石说^(8)---aminomethyl-butyrylamine hexahydro: cough and [3,2 -b]furan-3-ylthio]-ethenyl truncation, in the form of hydrochloride. For characterization data, see Table 5, Example 38a »

實例I-Q 14-0_[((3-(R/S)-胺基-環己-i—OR/s)·基）_硫基乙醯基）】_截短素，呈 鹽酸鹽形式 將已落於10毫升THF中之10.6克截短側耳素-22-0-甲苯磺酸 酯，慢慢添加至5.2克N-BOC-3-(R/S)-巯基-環己基胺與2 74克第 二-丁醇鉀在250毫升THF中之溶液内。將所得混合物攪拌2 小時，於鹽水與EtAc之間分配，並以0.1NHC1萃取。使所得 有機相脫水乾燥，蒸發溶劑，並使所得之蒸發殘留物接受 84364 -83- 1331916 層析。獲得14-0-[((N-B0C-3(R/S)-胺基-環己小⑻扑基）_硫基乙醯 基）]-截短素’並經由以含醚HC1處理，轉化成胺 基-環己-1-(R/S)-基）-硫基乙醯基）]-截短素，呈形式鹽酸鹽。1^· NMR (d6 -DMS0) 8.0 (b, 3H, NH3 +), 6.15,5.1 (2xm, Hi 9, H2 〇, H2 *,), 5.52 (d, 1H, J-5.2Hz, H! 4), 3.4 (m, 1H, Hj Y), 3.3 (m, 2H, H2 2), 2.9 (m, 1H, NCH), 2.7 (m, 1H, CHS), 1.18, 1.45 (2xs, (CH3 )i 5 &gt; (CH3 )t 8 ), 0.75,0.88 (2xd, (CH3)16,(CH3)17,J=5.4Hz) II.用於製備本發明（新穎）截短側耳素之中間物（起始物質）乏 製備 - 實例II-A 14-鲩基-乙醯基-截短素 II-AA) 14-0-[(碳胺基亞胯基硫基）乙醯某截钽素-甲节砝齡吨 將15.2克硫脲與106.4克截短側耳素_22_〇·曱苯磺酸酯在25〇 毫升丙嗣中之溶液’於回流下加熱丨_5小時，移除溶劑，並 添加1〇〇毫.升己烷《形成沉澱物，過濾，及乾燥。獲得14_〇_[( 碳胺基亞胺基硫基）乙酿基]截短素_甲苯續酸酿。 II-AB) 14-酿基-乙醯某-截短素 將4.7克NadsO5在25毫升H：2〇中之溶液，添加至122克14 〇_[( 碳胺基亞胺基硫基）乙醯基]截短素_甲苯磺酸酯在2〇毫升Et〇H 與35毫升氏0混合物中之溶液（溫熱至約9〇0)内。將ι〇〇毫升 CCI4添加至所得反應混合物中，並將所得混合物於回流下加 熱約2小時。分離所得之兩相系統，使有機相乾燥，並蒸發 溶劑。獲得14-巯基-乙醯基-截短素。 實例II_B N-BOC-3(R)_甲磺醯基氧基·六氫吡啶 II-BA) N-BOC-3(RV與某-六氣毗冷 84364 -84- 1331916 將3·48克3-(R)-經基六氫吡啶、8.72克二碳酸二-第三丁酯及4 克N-甲基-嗎福啉在70毫升二氧陸圜中之懸浮液，於室溫下 攪拌18小時。使溶劑自所得混合物中蒸發，並使所得之蒸 發殘留物溶於CH2C12中，且以1NHC1萃取。使所得有機相脫 水乾燥，並蒸發溶劑。獲得N-BOC-3(R)-羥基-六氫吡啶。 II-BB) N-BOC-3(RV甲續酿基氣基-六氮叶匕咬 將5.08克N-BOC-3(R)-羥基-六氫吡啶與8.7克甲烷磺酸酐在100 毫升p比淀中之溶液，於室溫下揽拌22小時，蒸顧出ρ比咬， 使蒸餾殘溜物溶於CH2C12中，將所得混合物以1NHC1萃取， 使所得有機相脫水乾燥，蒸發溶劑，並使所得之蒸發殘留 物接受層析。獲得N-BOC-3(R)-甲磺醯基氧基-六氫吡啶。1!!-NMR (CDC13)： 4.7 (m, 1H, CH0S02 CH3), 3.2-3.6 (m, 4H, CHN), 3.0 (s, 3H, CH3 S02)，1.4 (m，9H，第三丁基）· 實例II-C N-BOC-六氫吡啶-3(S)-硫醇 II-CA) N-BOC-3-(Sy硫基乙酿氣基-六氫峨咬 將2.2克N-BOC-3-(R)-羥基-六氫吡啶在10毫升THF中之溶液， 於氬氣下，與1毫升硫酷酸，一起添加至3.4克三苯膦與2.65 毫升氮二碳酸酸-異丙氧基化物在1〇毫升THF中之溶液内。 將所得混合物於70。下保持18小時，蒸發溶劑，並使所得之 蒸發殘留物接受層析。獲得N-BOC-3-(S)-硫基乙醯氧基-六氫 ψ 吡啶。iH-NMRCCDCl〗）： 3_78(dd，lH，NCH2CHS，J=3.1Hz，J=13.3Hz)， 3.5-3.6 (m，2H，CHSC=ONCH2CH2)，2·32 (s，3H，SOOCH3)，1.46 (s，9H，第 三丁基） II-CB) N-BOC-六氫吡啶-3(SV硫醇 84364 -85- 1331916 於259毫克N-B0C-3-(S)-硫基乙醯氧基-六氫吡啶在10毫升 MeOH中之溶液内，添加262毫克NaSCH3在5毫升MeOH中之溶 液，並將所得混合物攪拌2小時，蒸發溶劑，及使所得之蒸 發殘留物於EtAc與HC1水溶液之間分配。使溶劑自所得之有 機相中蒸發。獲得N-BOC-六氫吡啶-3(S)-硫醇。1H-NMR (d6 -DMSO) :2.6 (d，1H, SH，J=7.2Hz), 2.9-2.7 (m, 3H，NCH2，CHS)，1.35 (b, 9H，第三 丁基）.MS (ESI) 457 (2M+Na). 實例II-D 3-(N-BOC-(R)-異纈草胺醯基-胺基)-環己烷-(R/S)-硫醇 II-DA) 3-(R/SM2,4,6-三甲基-芊基-硫基V環己酮 將3.32克2,4,6-三甲基-芊基硫醇與3.84克環己烯-3-酮在30毫 升吡啶中之溶液，於40°下加熱3小時。將所得混合物倒入200 毫升1MHC1中，並以CH2C12萃取所得混合物。使所得有機相 脫水乾燥，蒸發溶劑，並使蒸發殘留物於碎膠上接受層析 。獲得3-(R/S)-(2,4,6-三甲基-苄基-硫基）-環己酮。1H-NMR(d6-DMSO) : 6.8 (s，2H，芳族 H)，3.8 (s，2H，C6H5 CH2 S-)，3.3 (m，1H，CHS)， 3.18 (dd, 1H, CHC=NOH, J=4Hz, 13.9Hz), 2.65-2.8, 2.44-2.49 (2xm, 4H, CH2C=OCH2), 2.15, 2.3 (9H, 3xCH3). II-DB) 3-(R/SH2,4.6-三甲基-芊基-硫基V環己酮-肋（同側與對側 形式） 將5.24克3-(R/S)-(2,4,6-三曱基-芊基-硫基）-環己酮、1.38克呈鹽 酸鹽形式之羥胺及2克三乙胺在50毫升MeOH中之溶液，於25° 下攪拌12小時，將所得混合物倒入200毫升鹽水中，並以 CH2C12萃取所得混合物。使所得有機相脫水乾燥，並蒸發溶 劑。使所得之3-(R/S)-(2,4,6-三甲基-苄基-硫基）環己酮-肋之同側 84364 -86- 1331916 與對側形式之混合物接受層析。獲得純同側與純對側之3-(R/S)-(2,4,6-三甲基-芊基-硫基）-環己酮-月亏。 同側形式之1 H-NMR (d6 -DMSO) : 10.3 (s，1Η，0H)，6.8 (s, 2H，芳族 H)， 3.75 (s, 2H, C6H5CH2S-), 2.88 (m, 1H, CHS), 3.18 (dd, 1H, CHC=NOH, J= 4Hz, 13.9Hz), 2.13 (dd, 1H, CHC=NOH, J=5.2Hz, 13.9Hz), 2.15, 2.3 (9H, 3xCH3 )· 對側形式之1 H-NMR (d6 -DMSO) : 10·3 (s，1H，OH), 6·8 (s，2H,芳族 H)， 3.75 (s, 2H, C6H5CH2 S-), 2.92 (m, 1H, CHS), 2.58 (dd, 1H, CHC=NOH, J=' 4Hz, 13.9Hz&gt;, 2.15 (dd, 1H, CHC=NOH, J=4.2Hz, 13.6Hz), 2.15, 2.3 (9H, 3xCH3). II-DC) 3-(R/SM2,4,6-三曱基-芊基-硫基V環己基-(R/SV胺 將2.7克3-(R/S)-(2,4,6-三曱基-苄基-硫基）-環己酮-Μ添加至20 毫升1Μ LiAlH3溶液與15毫升二氧陸圜之混合物中，將所得混 合物於80°·下加熱1小時，並將所得混合物倒入200毫升20% NH4C1水溶液中。以EtAc萃取所得混合物，使所得有機相脫 水乾燥，並蒸發溶劑。獲得3-(R/S)-(2,4,6-三甲基-宇基-硫基）-環 己基-(R/S)胺。 II-DC) 3-(N-BOC-q〇-異纈箪胺醯基-胺基V環己-1-0R/SV基-硫基曱 某-(2A6-三甲基-笨） 將1.05克3-(R/S)-(2,4,6-三甲基-宇基-硫基）-環己基-(R/S)-胺、870 毫克BOC-R-纈胺酸、760毫克EDC及404毫克三乙胺在20毫升 THF中之混合物，於室溫下攪拌2小時。使所得混合物於鹽 水與EtAc之間分配，使所得有機相脫水乾燥，蒸發溶劑，並 使蒸發殘留物接受層析。獲得3-(N-BOC-(R)-異纈草胺醯基-胺 84364 -87- 1331916 基）-環己-1-(R/S)-基-疏基曱基-(2,4,6-三曱基-苯）。iH-NMR%- DMSO):旋轉異構物，7.78, 7.3, 6.52 (3xd，2H，NH)，J=7.9Hz)，6.8, 6.82 (2xs，2H，芳族 Η), 6.55 (m，1H，NHC=0)，3.7 (m，1H，a-H-異纈草胺醯基）， 3_6 (m，1H，NHCH)，2_75, 3.0 (2xm，1H，CHS)，1.39 (s，9H，第三 丁基） 3-(N-BOC-(R)-異纈草胺醯某-胺基環己烷-(r/SV硫醉 使10毫升氨在-70。下，於600毫克3-(N-BOC-(R)-異纈草胺醯基 -胺基）-環己-1-(R/S)-基-硫基甲基_2,4,6_三曱基-苯在15毫升THF 中之溶液内凝結’並分次添加鋼，直到溶液保持深藍色、 止。將固體NI^Cl添加至所得混合物中，並使所得混合物溫 熱至室溫，以氮沖洗，濾出所得之固體殘留物，使所得遽 液濃縮，並使其於矽膠上接受層析。獲得3-(N-BOC-(R)-異纈 草胺醯基-胺基）-環己烷-(R/S)-硫醇。iH-NMRCd^DMSO):旋轉 異構物，7.75 (m，1H，NHCHC=0)，6_55 (m，1H，NHC=0)，2.75 (m，1H，CHS)， 2.58 (d，1H，SH，J=6.6Hz)，1.39 (s，9H，第三 丁基） 類似如實例II-D中所陳述之方法，但使用適當起始物質， 獲得下列化合物： 實例Π-D-l N-BOC-3-(R/S)·疏基·環己胺 實例Π-D·2 4_(R/S)-疏基-一氣七園虎-2-嗣 得自4-(R/S)-(2,4,6-三甲基-爷基-硫基）-一氮七圜烷·2-酮。4-NMR (d6 -DMSO) : 6.15, 5.1 (2xm，氏 9，Η2。，H2 i )，5.52 (d，1Η，J=5.2Hz， % 4)，3.4 (m，1H，Η! i )，3.3 (m，2H，H2 2)，2.99-3.12 (b，2H，CH2N)，3.18 (m， 1H, SCH), 2.7 (m, 1H, C=OCH), 2.67 (d, 1H, SH, J=5.5Hz), 2.58 (d, 1H, C=OCH，J=13.5Hz)，U8, 1.45 (2xs，（CH3)! 5，（CH3 h 8 )，0.75,0.88 (2xd， (CH3 )2 6, (CH3 )! 7, J=5.4Hz). 84364 •88- 1331916 實例Π-E N-BOC-3-(R/SH2,4,6-三甲基-竿基硫基)-環己基-〇R/S)-胺 將11克3-(R/S)-(2,4,6-三甲基-爷基-硫基環己胺、9.15克BOC-酐及4.2克三乙胺在1〇〇毫升THF中之溶液，於25〇下攪拌12小 時’蒸發溶劑，並使已濃縮之殘留物於CH2 Cl2與1M HC1之間 分配。使溶劑自所得有機相中蒸發，並使蒸發殘留物接受 層析。獲得N-BOC-3-(R/S)-(2,4,6-三曱基-字基-硫基）-環己基-(R/S)-胺。1H-NMR(d6-DMSO): 6.81，(3，出，_^0)，6.8(3,211，芳族印，3.75(3, 2H, C6H5CH2S-), 3.2 (m, 1H, CHN), 2.70 (m, 1H, CHS), 2.13 2.15, 2.3 (9H； 3xCH3)，1.4_(s，9H，第三 丁基） 實例II-F甲苯-4-磺酸（38&gt;8,611加11)-6-羥基-六氫-咬喃并[3,2-1)] 嗅喃-3-基醋與甲苯-4-績酸（311，338,68,6211)-6-幾&gt;基，六氫-咬喃并 [3,2-b】呋喃-3-基酯 將 8.76 克（3S，3aS，6R，6aR)-六氫-吱喃并[3,2-b]吱喃-3,6-二醇在 80 毫升峨咬中之溶液’與13.7克氯化甲苯續醯，一起攪拌if小 時，蒸餾出溶劑，並使蒸餾殘留物溶於EtAc中，且以IN HC1 、飽和NaHC03水溶液及H20萃取。使所得肴機層脫水乾燥， 蒸發溶劑，並使蒸發殘留物接受層析。獲得曱苯-4-續酸 (3S，3aS，6R，6aR)-6-羥基-六氫-吱喃并[3,2-b]呋喃-3-基酯⑷與曱苯-4-績酸^尺^呂讲/设^-經基-穴氫-吱喃并^冲夫喃^-基酉旨⑼》 形式（a)之1 HNMR(DMSO-d6) : 7.8(d，2H，Ar-H，J=8.2Hz)，7.5(d，2H，Example IQ 14-0_[((3-(R/S)-Amino-cyclohexan-i-OR/s)-yl)-thioethyl)-- truncation, in the form of hydrochloride 10.6 g of pleuromutilin-22-0-tosylate, which had fallen in 10 ml of THF, was slowly added to 5.2 g of N-BOC-3-(R/S)-mercapto-cyclohexylamine and 2 74 A solution of the second potassium butoxide in 250 ml of THF. The resulting mixture was stirred for 2 h, partitioned between brine and EtOAc (EtOAc). The resulting organic phase was dried to dryness, the solvent was evaporated, and the obtained evaporation residue was subjected to chromatography from 84364 - 83 - 1331916. Obtaining 14-0-[((N-B0C-3(R/S)-Amino-cyclohexyl (8) fluorenyl)-thioethenyl)]- truncated ' and treated via ether-containing HC1, Conversion to the amine-cyclohexan-1-(R/S)-yl)-thioethenyl)]- truncation, in the form of the hydrochloride salt. 1^· NMR (d6 -DMS0) 8.0 (b, 3H, NH3 +), 6.15, 5.1 (2xm, Hi 9, H2 〇, H2 *,), 5.52 (d, 1H, J-5.2Hz, H! 4 ), 3.4 (m, 1H, Hj Y), 3.3 (m, 2H, H2 2), 2.9 (m, 1H, NCH), 2.7 (m, 1H, CHS), 1.18, 1.45 (2xs, (CH3 )i 5 &gt; (CH3 )t 8 ), 0.75, 0.88 (2xd, (CH3)16, (CH3)17, J=5.4Hz) II. Intermediate for the preparation of the novel (novel) pleuromutilin of the invention (from Preparation of starting material - Example II-A 14-mercapto-ethenyl-truncated II-AA) 14-0-[(carbamoyl fluorenylthio) acetamidine砝 吨 将 1 5.2 1 1 1 1 1 1 1 1 1 1 1 1 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 5.2 1 〇〇 . liter of hexane "formation of precipitates, filtration, and drying. 14_〇_[(Carbominoimidothio)ethyl ketone] truncation _ toluene acid was obtained. II-AB) 14-Banky-Ethyl-T-Truncation A solution of 4.7 g of NadsO5 in 25 ml of H:2 hydrazine was added to 122 g of 14 〇_[(carbamoiminothio)ethyl A solution of thiol] truncation-tosylate in 2 ml of a mixture of Et〇H and 35 ml of 0 (warmed to about 9 〇 0). 〇〇 ml of CCI4 was added to the obtained reaction mixture, and the resulting mixture was heated under reflux for about 2 hours. The resulting two phase system was separated, the organic phase was dried, and the solvent was evaporated. 14-mercapto-ethenyl- truncation was obtained. Example II_B N-BOC-3(R)_Methanesulfonyloxy-hexahydropyridine II-BA) N-BOC-3 (RV with a certain - six gas adjoining cold 84364-84-1331916 will be 3.48 g 3 a suspension of -(R)-pyridylpiperidine, 8.72 g of di-tert-butyl dicarbonate and 4 g of N-methyl-morphine in 70 ml of dioxane, stirred at room temperature 18 The solvent was evaporated from the obtained mixture, and the obtained evaporation residue was dissolved in CH.sub.2 C.sub.2, and extracted with &lt;1&gt; Hexahydropyridine. II-BB) N-BOC-3 (RV methyl ketone-hexanitrozepine bite 5.08 g N-BOC-3(R)-hydroxy-hexahydropyridine and 8.7 g methanesulfonic anhydride The solution was stirred at room temperature for 22 hours at room temperature, and the distillation residue was dissolved in CH2C12. The obtained mixture was extracted with 1NHC1, and the obtained organic phase was dried and dried. The solvent was evaporated, and the obtained residue was purified eluted eluted elute elute elute elute elute elute CH0S02 CH3), 3.2-3.6 (m, 4H, CHN), 3.0 (s, 3H, CH3 S02), 1.4 (m, 9H, Tributyl)·Example II-C N-BOC-Hexahydropyridine-3(S)-thiol II-CA) N-BOC-3-(Sy thioethyl ethoxylate-hexahydro hydrazine bite 2.2 g A solution of N-BOC-3-(R)-hydroxy-hexahydropyridine in 10 ml of THF was added to 3.4 g of triphenylphosphine and 2.65 ml of nitrogen dicarbonate together with 1 ml of sulphuric acid under argon. - Isopropoxylate in a solution of 1 mL of THF. The obtained mixture was kept at 70 ° for 18 hours, the solvent was evaporated, and the obtained residue was subjected to chromatography to give N-BOC-3-(S). )-thioethyloxy-hexahydropyridinium pyridine. iH-NMRCCDCl): 3_78 (dd, lH, NCH2CHS, J = 3.1 Hz, J = 13.3 Hz), 3.5-3.6 (m, 2H, CHSC = ONCH2CH2) ), 2·32 (s, 3H, SOOCH3), 1.46 (s, 9H, tert-butyl) II-CB) N-BOC-hexahydropyridine-3 (SV mercaptan 84364-85-1331916 in 259 mg N -B0C-3-(S)-thioethenyloxy-piperidine in a solution of 10 ml of MeOH, a solution of 262 mg of NaSCH3 in 5 ml of MeOH was added, and the mixture was stirred for 2 hr. And the resulting evaporation residue was partitioned between EtAc and HCl aqueous solution. The solvent is allowed to evaporate from the organic phase obtained. N-BOC-hexahydropyridine-3(S)-thiol was obtained. 1H-NMR (d6-DMSO): 2.6 (d, 1H, SH, J = 7.2 Hz), 2.9-2.7 (m, 3H, NCH2, CHS), 1.35 (b, 9H, tert-butyl). ESI) 457 (2M+Na). Example II-D 3-(N-BOC-(R)-isoindicinyl-amino)-cyclohexane-(R/S)-thiol II-DA 3-(R/SM2,4,6-trimethyl-indenyl-thio V cyclohexanone 3.32 g of 2,4,6-trimethyl-mercaptothiol and 3.84 g of cyclohexene-3 a solution of the ketone in 30 ml of pyridine was heated at 40 ° for 3 hours. The resulting mixture was poured into 200 ml of 1 MH.sub.1, and the mixture was extracted with CH.sub.2 C12. The obtained organic phase was dried, evaporated, and evaporated. Chromatography was carried out on the gum to give 3-(R/S)-(2,4,6-trimethyl-benzyl-thio)-cyclohexanone. 1H-NMR (d6-DMSO): 6.8 ( s, 2H, aromatic H), 3.8 (s, 2H, C6H5 CH2 S-), 3.3 (m, 1H, CHS), 3.18 (dd, 1H, CHC=NOH, J=4Hz, 13.9Hz), 2.65- 2.8, 2.44-2.49 (2xm, 4H, CH2C=OCH2), 2.15, 2.3 (9H, 3xCH3). II-DB) 3-(R/SH2,4.6-trimethyl-indenyl-thio-V-cyclohexanone - ribs (i-side and contra-form) 5.24 g of 3-(R/S)-(2,4,6-tridecyl-fluorenyl-thio)-cyclohexanone, 1.38 g of the hydrochloride salt form It A solution of the amine and 2 g of triethylamine in 50 ml of MeOH was stirred at 25 ° for 12 hr, and the mixture was poured into 200 ml of brine, and the mixture was extracted with CH2C12. The obtained organic phase was dried and evaporated. The obtained 3-(R/S)-(2,4,6-trimethyl-benzyl-thio)cyclohexanone-ribbed side of the same side 84464-86-1331916 and the opposite side of the mixture receiving layer 3-(R/S)-(2,4,6-trimethyl-indolyl-thio)-cyclohexanone-yield of the same side and pure opposite side. -NMR (d6-DMSO): 10.3 (s,1 Η,0H), 6.8 (s, 2H, aromatic H), 3.75 (s, 2H, C6H5CH2S-), 2.88 (m, 1H, CHS), 3.18 (dd , 1H, CHC=NOH, J= 4Hz, 13.9Hz), 2.13 (dd, 1H, CHC=NOH, J=5.2Hz, 13.9Hz), 2.15, 2.3 (9H, 3xCH3)· 1 H- NMR (d6-DMSO): 10·3 (s, 1H, OH), 6·8 (s, 2H, aromatic H), 3.75 (s, 2H, C6H5CH2 S-), 2.92 (m, 1H, CHS) , 2.58 (dd, 1H, CHC=NOH, J=' 4Hz, 13.9Hz>, 2.15 (dd, 1H, CHC=NOH, J=4.2Hz, 13.6Hz), 2.15, 2.3 (9H, 3xCH3). II- DC) 3-(R/SM2,4,6-tridecyl-fluorenyl-thio-V cyclohexyl-(R/SV amine will be 2.7 g 3-(R/S)-(2,4,6- Mercapto-benzyl-thio)-cyclohexanone-oxime was added to a mixture of 20 ml of 1 Μ LiAlH3 solution and 15 ml of dioxane, and the resulting mixture was heated at 80 ° C for 1 hour, and the resulting mixture was poured. Into 200 ml of 20% NH4C1 aqueous solution. The resulting mixture was extracted with EtAc, and the obtained organic phase was dried over water and evaporated. 3-(R/S)-(2,4,6-Trimethyl-ykyl-thio)-cyclohexyl-(R/S)amine was obtained. II-DC) 3-(N-BOC-q〇-isoguanamine fluorenyl-amino V cyclohex-1-0R/SV-thiol--(2A6-trimethyl-stupid) 1.05 3-(R/S)-(2,4,6-trimethyl-ykyl-thio)-cyclohexyl-(R/S)-amine, 870 mg BOC-R-proline, 760 mg EDC and a mixture of 404 mg of triethylamine in 20 mL of THF were stirred at room temperature for 2 hr. The mixture was partitioned between brine and EtEtOAc, and the organic phase was dried, evaporated and evaporated. Chromatography to obtain 3-(N-BOC-(R)-isosporin-ylamine-84364-87-1331916-)-cyclohexan-1-(R/S)-yl-carbyl-yl-( 2,4,6-tridecyl-benzene). iH-NMR%-DMSO): rotamer, 7.78, 7.3, 6.52 (3xd, 2H, NH), J = 7.9 Hz), 6.8, 6.82 (2xs , 2H, aromatic Η), 6.55 (m, 1H, NHC=0), 3.7 (m, 1H, aH-isoammine oxime), 3_6 (m, 1H, NHCH), 2_75, 3.0 (2xm, 1H, CHS), 1.39 (s, 9H, tert-butyl) 3-(N-BOC-(R)-isoxachlor oxime-aminocyclohexane-(r/SV sulphur makes 10 ml of ammonia At -70, at 600 mg of 3-(N-BOC-(R)-isochlorinyl-amino-cyclohexan-1-(R/S)-yl-thiomethyl-2 , 4, 6_Tridecyl-benzene is coagulated in a solution of 15 ml of THF and steel is added in portions until the solution remains dark blue. The solid NI^Cl is added to the resulting mixture, and the resulting mixture is warmed to the chamber. After warming, rinsing with nitrogen, the obtained solid residue was filtered off, and the obtained mash was concentrated, and subjected to chromatography on silica gel to obtain 3-(N-BOC-(R)-isochlorinamide-amine. ))-cyclohexane-(R/S)-thiol. iH-NMRCd^DMSO): rotamer, 7.75 (m, 1H, NHCHC = 0), 6-55 (m, 1H, NHC = 0), 2.75 (m, 1H, CHS), 2.58 (d, 1H, SH, J = 6.6 Hz), 1.39 (s, 9H, tert-butyl) analogously as described in Example II-D, but with appropriate use Starting from the starting material, the following compounds were obtained: Example Π-Dl N-BOC-3-(R/S)·Siliary·Cyclohexylamine Example Π-D·2 4_(R/S)-Silige-Iqiqiyuanyuan- 2-嗣 was obtained from 4-(R/S)-(2,4,6-trimethyl-ylidene-thio)-nitrosopenoxane-2-one. 4-NMR (d6-DMSO): 6.15, 5.1 (2xm, 9, and Η2. , H2 i ), 5.52 (d, 1Η, J=5.2Hz, % 4), 3.4 (m, 1H, Η! i ), 3.3 (m, 2H, H2 2), 2.99-3.12 (b, 2H, CH2N ), 3.18 (m, 1H, SCH), 2.7 (m, 1H, C=OCH), 2.67 (d, 1H, SH, J=5.5Hz), 2.58 (d, 1H, C=OCH, J=13.5Hz) ), U8, 1.45 (2xs, (CH3)! 5, (CH3 h 8 ), 0.75, 0.88 (2xd, (CH3)2 6, (CH3)! 7, J=5.4Hz). 84364 •88- 1331916 Examples Π-E N-BOC-3-(R/SH2,4,6-trimethyl-decylthio)-cyclohexyl-fluorene R/S)-amine will give 11 g of 3-(R/S)-( a solution of 2,4,6-trimethyl-y-yl-thiocyclohexylamine, 9.15 g of BOC-anhydride and 4.2 g of triethylamine in 1 mL of THF, stirred at 25 Torr for 12 hours. And the concentrated residue was partitioned between CH2Cl2 and 1M HCl. The solvent was evaporated from the obtained organic phase, and the residue was subjected to chromatography to obtain N-BOC-3-(R/S)-( 2,4,6-trimethyl-yl-thio-cyclohexyl-(R/S)-amine. 1H-NMR (d6-DMSO): 6.81, (3, out, _^0), 6.8 (3,211, aromatic print, 3.75 (3, 2H, C6H5CH2S-), 3.2 (m, 1H, CHN), 2.70 (m, 1H, CHS), 2.13 2.15, 2.3 (9H; 3xCH3), 1.4_(s, 9H, tert-butyl) Example II-F toluene- 4-sulfonic acid (38 &gt; 8,611 plus 11)-6-hydroxy-hexahydro-trinute[3,2-1)] ranol-3-yl vinegar and toluene-4-producing acid (311,338,68 , 6121)-6-some&gt;, hexahydro-trinop[3,2-b]furan-3-yl ester will 8.76 g (3S,3aS,6R,6aR)-hexahydro-indole[ A solution of 3,2-b]pyran-3,6-diol in an 80 ml bite was continuously stirred with 13.7 g of toluene chloride, stirred for an hour, the solvent was distilled off, and the distillation residue was dissolved in EtAc. And extracted with IN HC1, saturated aqueous solution of NaHCO3 and H20. The obtained layer was dehydrated and dried, the solvent was evaporated, and the evaporation residue was subjected to chromatography to obtain toluene-4-supply acid (3S, 3aS, 6R, 6aR) )-6-Hydroxy-hexahydro-indolo[3,2-b]furan-3-yl ester (4) and indole benzene-4-producing acid^foot^^^^^^^^^^^^^^^^^^^^^^^^^^^^并和^冲夫喃^-基酉(9) Form 1 (a) 1 HNMR (DMSO-d6): 7.8 (d, 2H, Ar-H, J = 8.2 Hz), 7.5 (d, 2H,

Ar-H, J=8.6Hz), 4.95 (d, 1H, 6-OH), 4.8 (m, 1H, H-3), 4.42 (dd, 1H, H-6a, J= 4.6 與 4.8Hz)，4.38 (d，1H, H-3a，J=4.6), 4.08 (m，1H，H-6), 3.8 (m, 2H, 2xH-2)， 3.7, 3.25 (2xdd, 2H, 2xH-5), 2.4 (s, 3H, Ar-CH3). 形式（b)之1 HNMR(DMSO-d6) : 7.8(d，2H，Ar-H，J=8.6Hz)，7.5(d，2H， 84364 -89- 1331916Ar-H, J=8.6Hz), 4.95 (d, 1H, 6-OH), 4.8 (m, 1H, H-3), 4.42 (dd, 1H, H-6a, J= 4.6 and 4.8 Hz), 4.38 (d,1H, H-3a, J=4.6), 4.08 (m,1H,H-6), 3.8 (m, 2H, 2xH-2), 3.7, 3.25 (2xdd, 2H, 2xH-5), 2.4 (s, 3H, Ar-CH3). Form 1 (b) 1 H NMR (DMSO-d6): 7.8 (d, 2H, Ar-H, J = 8.6 Hz), 7.5 (d, 2H, 84364 -89- 1331916

Ar-H, J=8.6Hz), 5.15 (d6-0H, J=3.5), 4.9 (m, 1H, H-3), 4.45 (dd, 1H, H-3a, J=4.3 與 4.8Hz), 4.2 (d，1H, H-6a，J=4.3), 4.0 (m, 1H, H-6), 3.7 (m, 3H, H-2 與 2xH-5), 3.5 (dd, 1H, H-2, J=9.5 ^ 6.3Hz), 2.4 (s, 3H, Ar-CH3).Ar-H, J=8.6Hz), 5.15 (d6-0H, J=3.5), 4.9 (m, 1H, H-3), 4.45 (dd, 1H, H-3a, J=4.3 and 4.8Hz), 4.2 (d,1H, H-6a, J=4.3), 4.0 (m, 1H, H-6), 3.7 (m, 3H, H-2 and 2xH-5), 3.5 (dd, 1H, H-2 , J=9.5 ^ 6.3Hz), 2.4 (s, 3H, Ar-CH3).

實例Π-G N-BOC-4-幾基-六氫吡啶-3-硫醇、N-BOC-3·羥基-六氫吡啶_4_硫醇 將1克N-BOC-3,4-環氧基六氫ρ比咬、1.9克三苯基碎燒基硫醇 及0.7毫升三乙胺在12.5毫升THF中之溶液，於70〇下攪拌24小 時，並添加1.7克TBAF與0_9毫升醋酸。將所得混合物攪拌· 1 小時，並於鹽水與EtAc之間分配。使有機相脫水乾燥，蒸發 溶劑’並使所得之蒸發殘留物於矽膠上接受層析《獲得⑷： N-BOC-4-羥基-六氫吡啶-3-硫醇與（b): N-BOC-3-羥基-六氫吡咬_4_ 硫醇。 ⑻之1 H-NMR (CDC13) : 4.45, 4.12, 2.8 (3xm，3H，CH2NCH)，3,31 (dt，1H， CHO, J=4.3Hz，J=10Hz)，2.65, 2.6 (2xm，2H, CHN，CHS)，1.5 (s，9H,第三丁 基)· (b)之1 H-NMR (CDC13) : 4.25, 3.45 2.7,（3xm，3H, CH2NCH)，3.2 (m, 1H, CHO)，2.55 (m, 2H，NCH，CHS)，1.5 (s，9H,第三丁基）.Example Π-G N-BOC-4-decyl-hexahydropyridine-3-thiol, N-BOC-3·hydroxy-hexahydropyridine-4-thiol 1 g N-BOC-3,4-ring A solution of oxyhexahydro ρ, 1.9 g of triphenylcalcyl mercaptan and 0.7 ml of triethylamine in 12.5 ml of THF was stirred at 70 Torr for 24 hours, and 1.7 g of TBAF and 0-9 ml of acetic acid were added. The resulting mixture was stirred for 1 hour and partitioned between brine and EtOAc. The organic phase is dehydrated and dried, the solvent is evaporated, and the obtained evaporation residue is subjected to chromatography on silica gel to obtain (4): N-BOC-4-hydroxy-hexahydropyridine-3-thiol and (b): N-BOC -3-hydroxy-hexahydropyrazole_4_ mercaptan. (8) 1 H-NMR (CDC13): 4.45, 4.12, 2.8 (3xm, 3H, CH2NCH), 3, 31 (dt, 1H, CHO, J=4.3Hz, J=10Hz), 2.65, 2.6 (2xm, 2H , CHN, CHS), 1.5 (s, 9H, tert-butyl) · (b) 1 H-NMR (CDC13): 4.25, 3.45 2.7, (3xm, 3H, CH2NCH), 3.2 (m, 1H, CHO ), 2.55 (m, 2H, NCH, CHS), 1.5 (s, 9H, tert-butyl).

試驗實例 實例A 結核分枝桿菌菌株抗藥性夕浪丨宗 已知化合物’異菸酸酊 '利福平及鏈黴素，抵抗如表A中 所列示結核分枝桿菌菌株1至14之活性，係在道脂稀釋試驗 中，根據如一般程序中所述之方法測得。MIC係在3、4及5 週後測定。已發現經測試之菌株1至7，對於異菸酸酊、利 84364 -90· 1331916 福平及/或鏈黴素，係為無論是敏感性⑸或抗藥性⑻。其 結果係如下文表A中所列示：EXPERIMENTAL EXAMPLES Example A Mycobacterium tuberculosis strain resistance The compound known as 'isonnacidal acid' rifampicin and streptomycin, resistant to the activity of M. tuberculosis strains 1 to 14 as listed in Table A In the lipid dilution test, it is measured according to the method as described in the general procedure. The MIC system was measured after 3, 4 and 5 weeks. Tested strains 1 to 7, which have been tested for bismuth isonicotinate, aliquot 84364-90·1331916, and/or streptomycin, have been found to be either sensitive (5) or resistant (8). The results are as listed in Table A below:

表ATable A

結核分枝桿菌 異於酸§1 利福平 P鏈擻素 菌株1 S S S 菌株2 S S S 菌株3 R R S 菌株4 R R R 菌株5 . R R S - 菌株6 S S S 菌株7 R S R 菌株8 S R S 菌株9 R S R 菌株10 S S S 菌株11 S S S 菌株12 S S S 菌株13 S S S 菌株14 S S S 菌株15 S S S 菌株15為生產菌株137kV。抗藥性與敏感性菌株係單離自 具有已知敏感性/抗藥性之病人。若菌株之MIC在根據一般 試驗程序之測試中，於3至5週後，係高於20微克/毫升， 則該菌株係被稱為抗藥性。Mycobacterium tuberculosis is different from acid §1 rifampicin P-staphylin strain 1 SSS strain 2 SSS strain 3 RRS strain 4 RRR strain 5 . RRS - strain 6 SSS strain 7 RSR strain 8 SRS strain 9 RSR strain 10 SSS strain 11 SSS strain 12 SSS strain 13 SSS strain 14 SSS strain 15 SSS strain 15 is a production strain of 137 kV. Drug resistant and susceptible strains are isolated from patients with known sensitivity/drug resistance. If the MIC of the strain is higher than 20 μg/ml after 3 to 5 weeks in the test according to the general test procedure, the strain is called drug resistance.

實例B #娜允合# (TC)抵抗如表A中所列示結核分枝桿菌菌株1 至5及7之活性，係於瓊脂稀釋試驗中，在如實例a之條件 下，於#娜化合场之不同瓊脂濃度中測定。MIC係在3、4及 84364 • 91 - 1331916 5週後測定。 下列#/效化合#(TC)之活性係經測試： 式I-提耳目林（Tiamulin)化合物： TC-1 式I-華臬目林（Valnemul·:!!)化合物： TC-2 式I-PREF1化合物： TC-3 式I-PREF2化合物： TC-4 式I-PREF3化合物： TC-5 式I-PREF4化合物： TC-6 式I-PREE5化合物： TC-7 式I-PREF6化合物： TC-8 式 I-PREF7 化合物·· TC-9 式I-PREF8化合物： TC-10 所獲得之試驗結果係列示於下文表B中：Example B #娜允合# (TC) resists the activity of M. tuberculosis strains 1 to 5 and 7 as listed in Table A, in the agar dilution test, under the conditions of Example a, in #娜化合Determined in different agar concentrations of the field. The MIC was measured after 5 weeks at 3, 4 and 84364 • 91 - 1331916. The following activities of #/化化#(TC) were tested: Formula I - Tiamulin Compound: TC-1 Formula I - Valnemul (:!!) Compound: TC-2 Formula I -PREF1 Compound: TC-3 Formula I-PREF2 Compound: TC-4 Formula I-PREF3 Compound: TC-5 Formula I-PREF4 Compound: TC-6 Formula I-PREE5 Compound: TC-7 Formula I-PREF6 Compound: TC -8 Formula I-PREF7 Compound·· TC-9 Formula I-PREF8 Compound: The series of test results obtained by TC-10 are shown in Table B below:

表B TC/週 抵抗以下菌株編號之結核分枝桿菌之MIC (微克/毫升） 1 .2 3 4 6 7 TC-1/3 5 5 5 5 10 10 TC-1/4 5 5 5 10 10 20 TC-1/5 5 5 5 10 10 20 TC-2/3 0.5 1 1 5 5 5 TC-2/4 0.5 5 1 5 5 5 TC-2/5 0.5 5 5 5 5 10 TC-3/3 1 5 5 1 5 20 TC-3/4 1 5 5 5 10 20 TC-3/5 1 5 5 10 10 20 TC-4/3 0.5 5 1 1 5 5 TC-4/4 1 5 1 5 5 5 84364 -92- 1331916 TC-4/5 1 ___5 5 5 5 5 TC-5/3 1 ^^ —5 5 5 5 一 TC-5/4 5 __5 ----- 5 5 10 10 TC-5/5 5 5 10 10 10 實例c 根據貫例B之方法進行。所獲得之試驗結果係列示於表c 與表D及表E中：Table B TC/week resistance to the MIC of the following strain number of M. tuberculosis (μg/ml) 1. 2 3 4 6 7 TC-1/3 5 5 5 5 10 10 TC-1/4 5 5 5 10 10 20 TC-1/5 5 5 5 10 10 20 TC-2/3 0.5 1 1 5 5 5 TC-2/4 0.5 5 1 5 5 5 TC-2/5 0.5 5 5 5 5 10 TC-3/3 1 5 5 1 5 20 TC-3/4 1 5 5 5 10 20 TC-3/5 1 5 5 10 10 20 TC-4/3 0.5 5 1 1 5 5 TC-4/4 1 5 1 5 5 5 84364 -92- 1331916 TC-4/5 1 ___5 5 5 5 5 TC-5/3 1 ^^ —5 5 5 5 One TC-5/4 5 __5 ----- 5 5 10 10 TC-5/5 5 5 10 10 10 Example c was carried out according to the method of Example B. The series of test results obtained are shown in Table c and Table D and Table E:

表C TC/週 抵1抗以下菌振总换4士从/^jjr招姑A/tTr1，规· * /客斗、 —1 ----- 2 ----y4 yP^. TT&quot;网一N·» , -Ci , | / 3 4 5 6 7 8 TC-2/3 0.5 4 ----- 4 · 8 2 4 4 4 TC-2/4*) 0.5 2 8 4 4 8 8 TC-4/3 1 ----^ 4 1 4 2 4 2 2 TC-4/4 2 4 ---- 1 4 2 4 4 2 TC-4/5 2 —1 4 2 4 4 4 --------1 )於31天後測試’且因此於5週後未進一步測試。Table C TC / week to 1 resistance to the following bacterial vibration total change 4 from / ^ jjr Zhao Gu A / tTr1, regulations · * / guest, -1 ----- 2 ----y4 yP^. TT&quot;网一N·» , -Ci , | / 3 4 5 6 7 8 TC-2/3 0.5 4 ----- 4 · 8 2 4 4 4 TC-2/4*) 0.5 2 8 4 4 8 8 TC-4/3 1 ----^ 4 1 4 2 4 2 2 TC-4/4 2 4 ---- 1 4 2 4 4 2 TC-4/5 2 —1 4 2 4 4 4 -- ------1) Tested after 31 days' and therefore not further tested after 5 weeks.

表D TC/週 菌株編號之結核分枝棵苗之MIC(微克/奎升） 10 11 12 14 TC-2/3 4 TC-2/4*) TC-4/3 TC-4/4 TC-4/5 4 2 4 4 4 2 4 4 4 2 2 2 2 2 4 2 2 4 4 4 4 2 2 4 )於31天後剛試，且因此於5週後未進一步測試 84364 -93- 1331916Table D MIC of TB/week strain number of tuberculosis seedlings (μg/Quin) 10 11 12 14 TC-2/3 4 TC-2/4*) TC-4/3 TC-4/4 TC- 4/5 4 2 4 4 4 2 4 4 4 2 2 2 2 2 4 2 2 4 4 4 4 2 2 4 ) Just tested after 31 days, and therefore no further testing after 8 weeks 84364 -93 - 1331916

表E TC/週 --- 抵抗以下菌株編號之結核分枝桿菌之MIC (微克/毫升） 1 12 15 .TC-6/2 1 1 0.5 ______TC-7/1 2 32 32 TC-8/1 2 32 32 __TC-9/l 8 32 32 s_TC-10/2 2 16 ----- 4 於表B至E中，在&quot;TC/週I，一攔中，，,TC_編號”一詞係表示 如上文定―義之㈣允舍#，例如TCM表示式[提耳目林化合 物，而’/週”係表示在此種m合勒測試中之mic測定點 (自:種起之週數)。例如&quot;卿&quot;係表示㈣耳㈣ &lt; IC ’係自接種起3週後測得。 C為如上文定義之最低抑制濃 編號！至4及6至7，於表 、表B中心K讀祙 D中指示之菌株株編號1至9 ’及於表 及心係ft 於表E中指示之菌株編號1 M2 再者^ 相應結核分枝㈣菌株。 式1^化合物與式ΓΕχ化合物，並 所定義者，亦已”顯示抵 ：Μ-係如下表6中 經測試之化合物均呈鹽酸鹽形式)株卜12及15之活性(所有 84364 -94 - 1331916 表6Table E TC/week---MIC of MIC (Mg/ml) against M. tuberculosis of the following strain number 1 12 15 .TC-6/2 1 1 0.5 ______TC-7/1 2 32 32 TC-8/1 2 32 32 __TC-9/l 8 32 32 s_TC-10/2 2 16 ----- 4 In Tables B to E, in the words &quot;TC/week I, one stop,,,, TC_number" It is expressed as the above (4) Yunshe #, for example, the TCM expression [Tiermin compound, and '/week" indicates the mic measurement point in this m-Muller test (from the number of weeks since the planting) . For example, &quot;Qing&quot; indicates that (4) the ear (4) &lt; IC ' is measured 3 weeks after the inoculation. C is the minimum suppression concentration number as defined above! To 4 and 6 to 7, strains No. 1 to 9' indicated in Table K, Table K, and the strain number indicated in Table E, M1 and then the corresponding tuberculosis Branch (four) strain. The compound of the formula 1^ and the compound of the formula, and which are defined, have also been shown to exhibit the activity of the compounds 12 and 15 (all of which are tested as follows: the compounds tested in Table 6 are in the form of the hydrochloride salt) (all 84364-94) - 1331916 Table 6

Rex Rex Rex 化合物 Ιεχ H3&lt;\ ch3 ch3 ch3 NH- 0 ch3 0〇v°h nh2 化合物 Ιεχ cr ^ NH2 〇A^YCH3 ch3 CT NH in3 V f · H〆&quot;丫〜T&quot;CH3 〇 CH3 ^匕合物 Ιεχ - cV nh2 cr 々〉 化合物 Ιεχ nh2 XT 化合物 Ι，ΕΧ XX 9H3 nh2 ch3 84364 95-Rex Rex Rex Compound Ιεχ H3&lt;\ ch3 ch3 ch3 NH- 0 ch3 0〇v°h nh2 Compound Ιεχ cr ^ NH2 〇A^YCH3 ch3 CT NH in3 V f · H〆&quot;丫~T&quot;CH3 〇CH3 ^匕ΙεΙ - cV nh2 cr 々> Compound Ιεχ nh2 XT Compound Ι, ΕΧ XX 9H3 nh2 ch3 84364 95-

Claims (1)

公告本 1331916 第092106937號專利申請案 中文申請專利範圍替換本(99年1 拾、申請專利範圍： 1. 一種化合物，其係選自包括如表1中所列示化學式之化合 物： 表1Announcement 1331916 Patent Application No. 092106937 Chinese Patent Application Renewal (99 years 1 patent application scope: 1. A compound selected from the group consisting of compounds including the chemical formulas listed in Table 1: Table 1 84364-990127.doc 133191684364-990127.doc 1331916 2. —種下式化合物，2. - a compound of the formula below, 其中 -虛線為無鍵結（單鍵介於位置3七之間），且R1A與R2A係互 相獨立為氫、鹵素或氘， 尺3八為（匚1_6)烧基， R4a為氫、（c丨_6)烷基、基團-c(=nh)-nh2，或胺基酸之殘基，Wherein - the dotted line is no bond (single bond between positions 3 and 7), and R1A and R2A are independent of each other as hydrogen, halogen or helium, and the ruler 3 is (匚1_6), R4a is hydrogen, (c丨_6) an alkyl group, a group -c(=nh)-nh2, or a residue of an amino acid, R4A與R5A—起為基團=ch-nh2， ^6Α為氫或氛，及 mA為2或3。 3. —種14-0-(羥亞胺基_(c3_8)環烷基-硫基曱基羰基）-戴短侧耳 素與14-0-(亞胼基_(c3_8)環烷基-硫基曱基羰基)-截短側耳素。 4. 一種下式化合物， 84364-990127.doc •2- 其中R4A and R5A are groups of =ch-nh2, ^6Α is hydrogen or atmosphere, and mA is 2 or 3. 3. - 14-0-(hydroxyimino-(c3_8)cycloalkyl-thiodecylcarbonyl)-Pleurotus and 14-0-(indenyl-(c3_8)cycloalkyl-sulfur Base carbonyl carbonyl) - pleuromutilin. 4. A compound of the formula: 84364-990127.doc •2- -虛線為一個鍵結（雙鍵介於位置a==b之間 尺2 B不存在， 或 Rl B為氫，且 •虛線為無鍵結（單鍵介於位置a_b之間），且&amp;與&amp;係互 相獨立為氫、画素或氛， R10B具有如中請專利範圍第2項中所^義^之意義， mB為〇、1、2、3、4或5， R3B為氫或（Ci_6)烷基， X“-〇_R4b 或-NRsbR^， 心3為氫或(Cl_6)烧基，視情況被基團-NR7BR8B取代， R5B與R6B係互相獨立為(Ci 4)烷基， R7B#R8B&amp;相獨立為（Ch)烧基，或 R7B與R8B和彼等所連接之氮原子一起形成具有5至8個产 員之脂族雜環基，及 衣 R9B為氫或(ClM)垸基， 5. —種下式化合物， 84364-990127.doc 1331916- The dotted line is a bond (the double bond is between position a==b, ruler 2 B does not exist, or Rl B is hydrogen, and • the dotted line is no bond (single bond is between position a_b), and &amp; And &amp; are independent of each other as hydrogen, pixels or atmosphere, R10B has the meaning of ^ in the second paragraph of the patent scope, mB is 〇, 1, 2, 3, 4 or 5, R3B is hydrogen or (Ci_6)alkyl, X"-〇_R4b or -NRsbR^, core 3 is hydrogen or (Cl_6) alkyl, optionally substituted by the group -NR7BR8B, R5B and R6B are independently (Ci 4) alkyl , R7B#R8B&amp; is independently (Ch) alkyl, or R7B together with R8B and the nitrogen atom to which they are attached form an aliphatic heterocyclic group having 5 to 8 births, and R9B is hydrogen or (ClM ) thiol, 5. — compound of the formula, 84364-990127.doc 1331916 其中 -虛線為一個鍵結（雙鍵介於位置a=b之間），R1C為氫，且 R2 C不存在，Where - the dotted line is a bond (double bond between positions a = b), R1C is hydrogen, and R2 C does not exist, _虛線為無鍵結（單鍵介於位置a-b之間），且R1C與R2C係互 相獨立為氫、齒素或氘， 具有如申請專利範圍第2項中所定義之意義，及 R3C為胺基、（Ci_4)烷胺基、二（Cl_4)烷胺基、胺基酸之殘基 、羥基或（C1M)烷氧基。 6. —種下式化合物，The dotted line is unbonded (single bond is between positions ab), and R1C and R2C are each independently hydrogen, dentate or ruthenium, having the meaning as defined in item 2 of the patent application, and R3C is an amine. a (Ci_4)alkylamino group, a di(Cl-4)alkylamino group, a residue of an amino acid, a hydroxyl group or a (C1M) alkoxy group. 6. - a compound of the formula below, 其中 -虛線為一個鍵結（雙鍵介於位置a=b之間），R1D為氫，且 R2 D不存在* 84364-990127.doc -4- 1331916 或 虛線為無鍵結（單鍵介於位置a_b之間），且尺1 d與R2d係互 相獨立為氫、鹵素或氣， R4D具有如申請專利範圍第2項中所定義之意義’及 R3d為4至8個環員之脂族雜環基，並包含一個氮原子作為 雜原子，或（C4-8)環烷基，該雜環基或環烷基係被羥基或 綱基取代。 7·根據中請專利範圍第2至6項中任—項之化合物，其係呈 鹽形式。 8.根據申請專利範園第2 $ 6 is 士， 寸〜莉•囷弟2至6項中任一項之化合物，其係作 為醫藥使用》 9·根據f請專利範圍第7項之化合物，其係作為醫藥使用。 10.種邊藥組合物’其包含根據申請專利範圍第2至7項中 任一項之化合物以及至少一種醫藥賦形劑。 11·根據申請專利範圍第1〇項之醫藥組合物其進一步包含 另一種醫藥活性劑。 12.根據中請專利範圍第2至7項中任—項之化合物其係用 於製備治療微生物疾病之藥劑。 13·-種用於治療微生物疾病之醫藥组合物，其包含有效量之 根據申請專利範圍第2至7項中任__項之化Μ。 84364-990I27.docWhere - the dashed line is a bond (double bond between positions a = b), R1D is hydrogen, and R2 D is not present * 84364-990127.doc -4- 1331916 or the dotted line is no bond (single bond between Between positions a_b), and the rulers 1d and R2d are independent of each other as hydrogen, halogen or gas, R4D has the meaning of 'as defined in the second paragraph of the patent application' and the R3d is 4 to 8 ring members of the aliphatic a cyclic group and containing a nitrogen atom as a hetero atom or a (C4-8)cycloalkyl group substituted by a hydroxy group or a aryl group. 7. A compound according to any one of items 2 to 6 of the scope of the patent application, which is in the form of a salt. 8. According to the patent application Fan Park No. 2 $6 is a compound of any one of the two to six of the two, which is used as a medicine. It is used as a medicine. 10. A medicinal composition comprising a compound according to any one of claims 2 to 7 and at least one pharmaceutical excipient. 11. The pharmaceutical composition according to claim 1 of the patent application further comprising another pharmaceutically active agent. 12. A compound according to any one of claims 2 to 7 of the patent application, which is for use in the manufacture of a medicament for the treatment of a microbial disorder. 13. A pharmaceutical composition for treating a microbial disorder, comprising an effective amount of a phlegm according to any of items 2 to 7 of the scope of the patent application. 84364-990I27.doc
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